Extended release compositions comprising pyridostigmine

ABSTRACT

Extended release pyridostigmine dosage forms, suitable for maintaining stable plasma concentrations with reduced or minimized initial burst release/dose dumping of pyridostigmine, are provided. The dosage forms include matrix tablets, gastroretentive tablets, and pellets, the latter being suitable for dosing in capsules, tablets, and sachets, as well as for sprinkling on foodstuffs. The disclosure also provides methods for improving patient compliance by administering once-a-day extended release pyridostigmine bromide dosage forms that provide a superior controlled drug release.

1. RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 16/445,110 (the '110 application), filed Jun. 18, 2019, whichis continuation-in-part of International Application No.PCT/US2018/038118, filed Jun. 18, 2018, which claims priority to U.S.Provisional Patent Application No. 62/520,796, filed Jun. 16, 2017. The'110 application also claims priority to U.S. Provisional PatentApplication No. 62/725,024, filed Aug. 30, 2018, and U.S. ProvisionalPatent Application No. 62/826,402, filed Mar. 29, 2019. The disclosuresof all applications noted above are hereby incorporated by referenceherein in their entireties.

2. TECHNICAL FIELD

The present disclosure provides extended release pyridostigminecompositions suitable for once-daily administration. The compositionsare administered as a single dosage unit/day (QD) to provide extendedrelease of pyridostigmine bromide for at least about 14 hours (e.g., atleast about 18 hours). Such extended release compositions areparticularly beneficial in overcoming the gastrointestinal (GI) sideeffects experienced with currently pyridostigmine products by providingand maintaining therapeutic plasma concentrations for extended timeperiods, e.g., at least about 14 hours. The extended releasepyridostigmine compositions of the disclosure include matrix tablets,gastroretentive tablets, and pellets, the latter being suitable fordosing in capsules, tablets, and sachets, and for sprinkling onfoodstuffs. In certain embodiments, the gastroretentive compositions ofthe disclosure include an immediate release (IR) layer (containingpyridostigmine bromide) and an extended release (ER) component. Theimmediate release layer minimizes the lag time associated with thepresence of an extended release component alone. The compositionsprovide therapeutic drug plasma concentrations for extended periods oftime; and the reduction/elimination of the initial burst release/dosedumping seen with marketed pyridostigmine products aids in reducing GIside effects. The extended release component provides and maintainstherapeutic plasma concentrations of the drug for a period of at leastabout 14 hours.

3. BACKGROUND

Pyridostigmine bromide is an active cholinesterase inhibitor that doesnot cross the blood-brain barrier. It works by increasing levels ofacetylcholine, a chemical released by motor neurons to activate muscles.It is commonly used in muscle tone recovery in myasthenia gravis (MG),postoperative functional bowel bloating, and urinary retention. It hasalso been approved for combat use by United States military personnel,i.e., pyridostigmine bromide has been approved by the U.S. Food and DrugAdministration (FDA) to increase survival after exposure to Soman “nervegas” poisoning.

The time-to-maximum peak plasma concentration of oral pyridostigmine is1-2 hours and its elimination half-life is about 3-5 hours.Pyridostigmine undergoes hydrolysis by the enzyme cholinesterase and ismetabolized in the liver. It is excreted in the urine as a combinationof unchanged drug and pyridostigmine metabolites. The bioavailability ofpyridostigmine is reported to be about 10-20% (NDA #020414). Due tosuboptimal pharmacokinetics of pyridostigmine, including a shortduration of action, MG patients must take multiple tablets, occasionallymultiple times a day. The patients experience “wearing off” of the drugand worsening of symptoms prior to the next dose, suffer from poortolerability at higher dose levels, and experience difficulty adheringto the required frequent dosing regimen.

The FDA has approved Valeant Pharmaceutical's MESTINON® (pyridostigminebromide injection, suspension, tablets, and extended release (ER)tablets) for the treatment of MG. The MESTINON® injection contains 5mg/ml pyridostigmine bromide; MESTINON® suspension contains 60mg/teaspoon pyridostigmine bromide; MESTINON® tablets contain 60 mgpyridostigmine bromide; and ER MESTINON® TIMESPAN® tablets contain 180mg pyridostigmine bromide. The average daily dose of pyridostigmine isten 60 mg tablets, ten teaspoons of suspension, or between one and three180 mg ER tablets, spaced to provide maximum relief. The ER 180 mgtablets are administered, as 1-3 tablets, depending upon severity of thecondition, once- or twice-daily with an interval of at least 6 hoursbetween doses.

The currently approved ER pyridostigmine products provide an initialburst release/dose dumping, followed by extended release of theremaining dose of pyridostigmine bromide. The approved ER formulationsrelease about 35-55% of pyridostigmine after one hour, about 65-85%after four hours, and about 85% after eight hours (in vitrodissolution). As approximately 40-50% of the drug can be released duringfirst hour with the approved/marketed ER product, it has limitedclinical utility. Presently marketed pyridostigmine products are plaguedby a spike in concentration, or dose dumping, while attempting tomaintain therapeutic plasma concentrations of the drug for extendedperiods of time. Initial burst release/dose dumping of the drug isassociated with various side effects, e.g., nausea, vomiting, diarrhea,abdominal cramps, fasciculations, weakness, increased peristalsis,increased salivation, increased bronchial secretions, miosis, anddiaphoresis. Such an initial spike in vivo, causing unwanted sideeffects, can be compared with in vitro release of at least about 50% ofthe pyridostigmine bromide within two hours of dissolution into adissolution medium mimicking gastric fluid conditions.

It is particularly desirable for MG patients to have a constant level ofpyridostigmine to improve therapeutic outcome and quality of life, andto reduce side effects. There remains a need for ER pyridostigminecompositions that are designed to prolong and maintain therapeuticplasma concentration of pyridostigmine, and minimize side effects, bycontrolling the initial burst release/dose dumping of the drug. Thereremains a need in the art for ER pyridostigmine compositions thatprovide a minimal lag time, provide extended release with minimalinitial burst release/dose dumping, and maintain a stable therapeuticplasma concentration of the drug for extended periods of time. Thereremains a need in the art for extended release pyridostigminecompositions containing an immediate release layer containingpyridostigmine bromide to eliminate the lag time, and an extendedrelease component to provide extended release with minimal initial burstrelease/dose dumping of the drug; for extended release pyridostigminecompositions that will allow for reduced frequency of administration ofthe composition, improve patient compliance, and reduce side effectsassociated with an unwanted initial burst in drug release/dose dumping;and for development of a once-a-day extended release pyridostigminecompositions that can provide an extended release for at least about 16hours (preferably about 24 hours), and reduce side effects associatedwith dose dumping of the drug.

4. SUMMARY

In certain embodiments, the present disclosure provides for agastroretentive dosage form comprising an immediate release layer and anextended release component, wherein the immediate release layercomprises between about 10 mg and about 60 mg pyridostigmine bromide,and the extended release component comprises a core and a permeableelastic membrane surrounding the core. The core comprises between about50 mg and about 400 mg pyridostigmine bromide; hypromellose in an amountof between about 5 wt % and about 35 wt %, based on the total weight ofthe core; succinic acid; a carbonate salt; and a bicarbonate salt. Thepermeable elastic membrane comprises a plasticizer in an amount ofbetween about 5 wt % and about 25 wt % of the membrane composition, anda copolymer based on ethyl acrylate, methyl methacrylate, andtrimethylammonioethyl methacrylate chloride in powder form (1:2:0.2), inan amount of between about 75 wt % and about 95 wt % of the membranecomposition, and wherein the dosage form provides an extended release ofpyridostigmine bromide for at least about 14 hours.

In certain other embodiments, the dosage form of the present disclosureprovides an in vitro release of between about 20% and about 35% of thepyridostigmine bromide within about 2 hours of dissolution in adissolution medium comprising pH 4.5 acetate buffer with 100 mM NaCl.

In certain embodiments, the dosage form of the present disclosure floatsin about 40 minutes or less in a dissolution medium comprising pH 4.5acetate buffer with 100 mM NaCl.

In certain embodiments, the dosage form of the present disclosure, whenin contact with gastric fluid, swells in about 60 minutes or less to asize that prevents its passage through pyloric sphincter.

In certain embodiments, the dosage form of the present disclosuremaintains its integrity in a swollen state for a period of at leastabout 14 hours.

In certain embodiments, the dosage form of the present disclosurefurther includes crospovidone as a wicking agent.

In certain embodiments, the carbonate and bicarbonate salts compriseCaCO₃ and NaHCO₃, respectively.

In certain embodiments, the plasticizer is triethyl citrate.

In certain embodiments, the dosage form further includes a seal coatbetween the permeable elastic membrane and the immediate release layer.

In certain embodiments, the dosage form does not include a seal coatbetween the core and the permeable elastic membrane.

In certain embodiments, the dosage form further includes an orificepassing through the permeable elastic membrane and the seal coat.

In certain embodiments, the dosage form is a tablet.

In certain embodiments, the dosage form is a tablet that is suitable foronce daily administration and is administered as a single tablet/day.

In certain embodiments, the hypromellose is a mixture of a low viscosityhypromellose and a high viscosity hypromellose. In certain embodiments,the low viscosity hypromellose has a viscosity of between about 80 mPa·sand about 120 mPa·s. In certain embodiments, the high viscosityhypromellose has a viscosity of between about, 2,700 mPa·s and about5,040 mPa·s.

In certain embodiments, the present disclosure provides for agastroretentive dosage form comprising an immediate release layer and anextended release component, wherein the immediate release layercomprises between about 10 mg and about 60 mg pyridostigmine bromide,and the extended release component comprises a core and a permeableelastic membrane surrounding the core. The core comprises between about50 mg and about 400 mg pyridostigmine bromide; a high viscosityhypromellose in an amount of between about 5 wt % and about 35 wt %,based on the total weight of the core; succinic acid; a carbonate salt;and a bicarbonate salt, wherein the high viscosity hypromellose has aviscosity of between about, 2,700 mPa·s and about 5,040 mPa·s; whereineach of sodium bicarbonate and calcium carbonate is present in equimolaramounts with respect to succinic acid; and wherein each of sodiumbicarbonate, calcium carbonate, and succinic acid is present in anamount of between about 1 wt % and about 10 wt %, based on the totalweight of the core. The permeable elastic membrane comprises aplasticizer in an amount of between about 5 wt % and about 25 wt % ofthe membrane composition, and a copolymer based on ethyl acrylate,methyl methacrylate, and trimethylammonioethyl methacrylate chloride inpowder form (1:2:0.2), in an amount of between about 75 wt % and about95 wt % of the membrane composition. The dosage form floats in about 40minutes or less in pH 4.5 acetate buffer with 100 mM NaCl.

In certain embodiments, the disclosure provides for a gastroretentivedosage form comprising a core and a permeable elastic membranesurrounding the core, wherein the core comprises between about 50 mg andabout 400 mg pyridostigmine bromide, hypromellose in an amount ofbetween about 5 wt % and about 35 wt %, based on the total weight of thecore, succinic acid, a carbonate salt, and a bicarbonate salt, whereinthe hypromellose has a viscosity of between about, 2,700 mPa·s and about5,040 mPa·s; each of sodium bicarbonate and calcium carbonate is presentin equimolar amounts with respect to succinic acid; and each of sodiumbicarbonate, calcium carbonate, and succinic acid is present in anamount of between about 1 wt % and about 10 wt %, based on the totalweight of the core. The permeable elastic membrane comprises aplasticizer in an amount of between about 5 wt % and about 25 wt % ofthe membrane composition, and a copolymer based on ethyl acrylate,methyl methacrylate, and trimethylammonioethyl methacrylate chloride inpowder form (1:2:0.2), in an amount of between about 75 wt % and about95 wt % of the membrane composition. The dosage form floats in about 40minutes or less in pH 4.5 acetate buffer with 100 mM NaCl, and thedosage form provides an extended release of pyridostigmine bromide forat least about 14 hours.

5. BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B depict schematic representations of pyridostigminepellets, with and without an immediate release drug layer. FIG. 1Adepicts a schematic representation of a pyridostigmine pellet containinga cellet core, an extended release drug layer, a seal coat and afunctional coat. FIG. 1B depicts a schematic representation of apyridostigmine pellet containing a cellet core, an extended release druglayer, a seal coat, a functional coat, a second seal coat, an immediaterelease drug layer, and an over coat.

FIGS. 2A and 2B depict schematic representations of pyridostigminematrix tablets. FIG. 2A depicts a schematic representation of apyridostigmine matrix tablets containing a matrix core containingpyridostigmine bromide, a functional coat and an over coat. FIG. 2Bdepicts a schematic representation of a pyridostigmine matrix tabletscontaining a matrix core containing pyridostigmine bromide, a functionalcoat, an immediate release drug layer containing pyridostigmine bromide,and an over coat.

FIGS. 3A and 3B depict schematic representations of pyridostigminegastroretentive tablets. FIG. 3A depicts a schematic representation of apyridostigmine gastroretentive tablet containing a core containingpyridostigmine bromide, a seal coat, a functional coat and an over coat.FIG. 3B depicts a schematic representation of a pyridostigminegastroretentive tablet containing a core containing pyridostigminebromide, a seal coat, a functional coat, an immediate release drug layercontaining pyridostigmine bromide, and an over coat.

FIG. 4 compares dissolution profiles of pyridostigmine bromide fromTablets 8, 9, and 10, in about 900 ml of pH 4.5 acetate buffer, usingUSP Apparatus I—Custom basket, at about 100 rpm and about 37° C.

FIG. 5 compares dissolution profiles of pyridostigmine bromide fromPellets 2 and 3, in 200 ml of 50 mM phosphate buffer at pH 6.8, usingUSP Apparatus II (Paddle), at about 50 rpm and about 37° C.

FIG. 6 compares dissolution profiles of pyridostigmine bromide fromPellets 9, 10, and 11, in 200 ml of 50 mM phosphate buffer at about pH6.8, using USP Apparatus II (Paddle), at about 50 rpm and about 37° C.

FIG. 7 compares dissolution profiles of Tablets 8, 13, and 14 in about900 ml of pH 5.0 acetate buffer containing 150 mM NaCl, using USPApparatus I (Custom Basket), at about 100 rpm and about 37° C. FIG. 7shows that Tablets 13 and 14 (containing hydroxypropyl methylcellulosein an amount of about 30% w/w of the tablet core; and equimolar amountsof succinic acid and each of the two gas-generating agents) exhibitabout 10-15% slower drug release compared to Tablet 8 (containinghydroxypropyl methylcellulose in an amount of about 20% w/w of thetablet core; and nonequimolar amounts of succinic acid and each of thetwo gas-generating agents).

FIG. 8 compares dissolution profiles of Tablets 13 and 14, each with andwithout a hole in the membrane/functional coat, and Tablet 8 (with ahole). The dissolution testing was conducted in about 250 ml of pH 3.0media containing about 100 mM NaCl, using USP Apparatus III (BIO-DIS),at about 25 dpm and about 37° C.

FIG. 9 compares dissolution profiles of Tablet 8 (with a hole; “8-H”),and Tablets 14 and 14A, each with a hole (“H”) and without a hole in themembrane. The dissolution testing was conducted in about 900 ml of pH5.0 acetate buffer containing about 150 mM NaCl, using USP Apparatus I(Custom Basket), at about 100 rpm and about 37° C.

FIG. 10 compares floating lag times of Tablets 8, 11, 13, and 15, with(“H”) and without a hole, at 200 mg functional coating weight gain, andTablets 8A, 11A, 13A, and 15A, with and without a hole, at 250 mgfunctional coating weight gain. The flotation studies were performedusing a Rotating Bottle method at about 5 rpm and about 37° C., in 200ml of a dissolution medium at about pH 4.5 comprising about 100 mM NaCl.

FIG. 11 compares volumetric expansion at flotation of Tablets 8, 11, 13,and 15, with (“H”) and without a hole, at 200 mg functional coatingweight gain, and Tablets 8A, 11A, 13A, and 15A, with and without a hole,at 250 mg functional coating weight gain. FIG. 11 demonstrates thattablets without a hole exhibit higher volume expansion compared totablets with a hole at flotation. The volume expansion studies wereperformed, using a Rotating Bottle method at about 5 rpm and about 37°C., in 200 ml of pH 4.5 dissolution medium containing about 100 mM NaCl.

FIG. 12 compares volumetric expansion, at 90 minutes, of Tablets 8, 11,13, and 15, with (“H”) and without a hole, at 200 mg functional coatingweight gain, and volumetric expansion, at one hour, of Tablets 8A, 11A,13A, and 15A, with and without a hole, at 250 mg functional coatingweight gain. FIG. 12 demonstrates that tablets without a hole exhibithigher volume expansion compared to tablets with a hole at both 90minutes and one hour. The volume expansion studies were performed, usinga Rotating Bottle method at about 5 rpm and about 37° C., in 200 ml ofpH 4.5 acetate buffer containing about 100 mM NaCl.

FIG. 13 compares volumetric expansion, and weight gain at 24 hours, ofTablets 8, 11, 13, and 15, with (“H”) and without a hole, at 200 mgfunctional coating weight gain. The volume expansion studies wereperformed, using a Rotating Bottle method at about 5 rpm and about 37°C., in 200 ml of pH 4.5 acetate buffer containing about 100 mM NaCl.FIG. 13 demonstrates that tablets containing 200 mg of crospovidone(e.g., Tablets 11/11-H and 15/15-H) exhibit higher weight upon dryingcompared with tablets containing 100 mg of crospovidone (e.g., Tablets8/8-H and 13/13-H).

FIG. 14 compares dissolution profiles of Tablets 8B, 15, 16, and 17without a hole, and Tablets 8, 8B, 15, 16, and 17 with a hole (“H”),using BIO-DIS method at about 20 dpm and about 37° C., in 250 ml of pH3.0 dissolution medium containing about 100 mM NaCl. FIG. 14demonstrates that tablets without a hole exhibit slower drug releaserates compared to tablets with a hole.

FIG. 15 shows the effect of crospovidone on release rates ofpyridostigmine from the gastroretentive compositions of the disclosure.FIG. 15 compares dissolution profiles of Tablets 8, 18, and 19 in about900 ml of pH 5.0 dissolution medium containing about 150 mM NaCl, 30 mMsodium acetate, and 17 mM acetic acid, using USP Apparatus I (CustomBasket), at about 100 rpm and about 37° C. FIG. 15 demonstrates thattablets containing 200 mg of crospovidone (Tablets 18 and 19) exhibitfaster drug release compared to a tablet containing 100 mg ofcrospovidone (Tablet 8).

FIG. 16 compares dissolution profiles of tablets containing a mixture ofBENECEL™ K4M PH DCand METHOCEL™ K100 Premium DC (Tablets 20 and 21) anda tablet containing BENECEL™ K4M PH DC only (Tablet 8) in about 900 mlof pH 5.0 acetate buffer containing about 150 mM NaCl, using USPApparatus I (Custom Basket), at about 100 rpm and about 37° C. FIG. 16demonstrates that tablets containing the mixture (Tablets 20 and 21)provide more controlled release compared to a tablet containing BENECEL™K4M PH DC only (Tablet 8).

FIG. 17 compares dissolution profiles of tablets (all with a hole (“H”))containing an immediate release drug layer (Tablet 23) and tablets withno immediate release drug layer (Tablets 8 and 22) in about 900 ml of pH5.0 acetate buffer containing about 150 mM NaCl, using USP Apparatus I(Custom Basket), at about 100 rpm and about 37° C. FIG. 17 demonstratesthat the tablet containing an immediate release drug layer (Tablet 23)eliminates lag time compared to those that do not contain an immediaterelease drug layer (Tablets 8 and 22).

FIG. 18 compares pharmacokinetic data for gastroretentive Tablet 8 (T₁),pellet composition (T₂), and marketed pyridostigmine products, e.g.,MESTINON® tablets (R₂) and ER MESTINON® (i.e., TIMESPAN)® tablets (R₁).

FIG. 19 provides schematic and photographic representations of thegastroretentive dosage form of the disclosure from its initial tabletform to its residue after drug release.

FIG. 20 compares pharmacokinetic data for gastroretentive Tablet 34,with a hole in the functional coat, under low fat-low calorie (LF-LC)breakfast conditions (Condition I) and high fat-high calorie (HF-HC)breakfast conditions (Condition II). FIG. 20 demonstrates that Tablet 34provides a therapeutic plasma concentration of pyridostigmine for atleast about 22 hours.

FIG. 21 compares pharmacokinetic data for gastroretentive Tablet 35,without a hole, under LF-LC breakfast conditions (Condition I) and HF-HCbreakfast conditions (Condition II). FIG. 21 demonstrates that Tablet 35provides a therapeutic plasma concentration of pyridostigmine for atleast about 22 hours.

FIG. 22 provides a steady state plasma concentration of pyridostigminebromide from Tablet 34, day 5, based on a steady state simulation forTablet 34 over a 5-day period. FIG. 22 demonstrates that Tablet 34 canprovide and maintain therapeutic plasma concentrations ofpyridostigmine, e.g., about 20 ng/ml, for a period of at least about 14hours.

FIG. 23 compares in vitro dissolution profiles of a tablet containing animmediate release drug layer (Tablet 34), tablet with no immediaterelease drug layer (Tablet 8), and MESTINON® TIMESPAN, in 50 mM 900 mlof pH 4.5 acetate buffer with 100 mM NaCl, using USP Apparatus I (CustomBasket), at about 100 rpm and about 37° C. FIG. 23 demonstrates thatTablet 34 exhibits a substantial decrease in (e.g., elimination of) lagtime compared to Tablet 8. FIG. 23 further demonstrates that Tablet 8(without IR drug layer) exhibits minimized initial burst release; andTablet 34 (with IR drug layer) provides an immediate release of atherapeutic amount of pyridostigmine bromide, with reduced initial burstrelease (less than about 35% drug release in about 2 hours) of the drug,compared to MESTINON® TIMESPAN.

FIG. 24 compares pharmacokinetic data for gastroretentive Tablet 34,with a hole in the functional coat, under LF-LC breakfast conditions(Condition I) and HF-HC breakfast conditions (Condition II), andMESTINON® TIMESPAN, under HF-HC breakfast conditions (Condition II).FIG. 24 demonstrates that MESTINON® TIMESPAN provides higher drug plasmaconcentrations between about 0 and 5 hours compared to Tablet 34 underConditions I and II. FIG. 24 further demonstrates that Tablet 34, underConditions I and II, provides higher drug plasma concentrations over anextended time period, e.g., about 7 hours or beyond, compared toMESTINON® TIMESPAN.

FIG. 25A provides volume expansion of Tablet 34 using Rotating Bottlemethod, at 5 rpm and 37° C., in 200 ml of 0.001 N HCL containing 10 mMNaCl. FIG. 25A demonstrates that the tablet exhibits 100% volumeexpansion at about 30 minutes, 200% volume expansion at about 1 hour,and 300% volume expansion at about 8 hours post-administration of thetablet into the dissolution medium.

FIG. 25B provides texture/compressibility force for Tablet 34 at varioustime points and corresponding volume expansions (see FIG. 25A), usingTA.XT^(Plus) apparatus. FIG. 25B demonstrates that the compression forcerequired to squeeze out the matrix core at 2 hours post-administration,at about 200% volume gain, was 30 N; at 8 hours post-administration, atabout 300% volume gain, was 18.3 N; and at 24 hours post-administration,at about 250% volume gain, was 4.1 N.

6. DETAILED DESCRIPTION

The presently disclosed subject matter provides extended releasepyridostigmine compositions suitable for once-daily administration. Incertain embodiments, the composition is suitable for twice-dailyadministration. In certain embodiments, the compositions of thedisclosure provide dual-controlled release, e.g., membrane-controlledand matrix-controlled extended release, of pyridostigmine bromide. Suchdual-controlled release results in maintaining therapeutic plasmaconcentration, with minimized dose dumping (minimized initial burstrelease) of pyridostigmine bromide, and possibly overcome thegastrointestinal side effects associated with the currently marketedextended release pyridostigmine products. In certain embodiments, thelag time associated with the extended release compositions of thedisclosure is eliminated with the presence of an immediate release layercontaining pyridostigmine bromide. In certain embodiments, the extendedrelease compositions containing an IR layer minimize initial burstrelease of the drug compared to marketed extended release pyridostigmineproducts. The extended release pyridostigmine compositions of thedisclosure can be formulated as gastroretentive tablets, matrix tablets,and pellets suitable for dosing in capsules, tablets, sachets, and assprinkled pellets on food. In certain embodiments, the pyridostigminecompositions can be formulated as gastroretentive tablets providingextended release of pyridostigmine bromide. In certain embodiments, thecompositions of the disclosure provide extended release ofpyridostigmine bromide for at least about 14 hours, at least about 16hours, at least about 18 hours, or at least about 24 hours. In certainembodiments, the disclosure provides methods for making matrix tablets,pellets, and gastroretentive tablets comprising pyridostigmine bromide.

For clarity and not by way of limitation, this detailed description isdivided into the following sections:

6.1. Definitions;

6.2. Pyridostigmine Dosage Forms;

6.3. Methods of Making; and

6.4. Methods of Treatment.

6.1. Definitions

The terminology used in the present disclosure is for the purpose ofdescribing particular embodiments only and is not intended to belimiting. As used herein, the use of the word “a” or “an” when used inconjunction with the term “comprising” in the claims and/or thespecification can mean “one,” but it is also consistent with the meaningof “one or more,” “at least one,” and “one or more than one.” Stillfurther, the terms “having,” “including,” “containing,” and “comprising”are interchangeable, and one of skill in the art is cognizant that theseterms are open-ended terms.

As used herein, “and/or” refers to and encompasses any and all possiblecombinations of one or more of the associated listed items. The term“about” or “approximately” means within an acceptable error range forthe particular value as determined by one of ordinary skill in the art,which will depend in part on how the value is measured or determined,i.e., the limitations of the measurement system. For example, “about”can mean within 3 or more than 3 standard deviations, per the practicein the art. Alternatively, “about” can mean a range of up to 20%, up to15%, up to 10%, up to 5%, up to 1%, up to 0.5%, or even up to 0.1% of agiven value. Unless otherwise defined, all terms, including technicaland scientific terms used in the description, have the same meaning ascommonly understood by one of ordinary skill in the art to which thepresent disclosure belongs. As used herein, “about” will be understoodby persons of ordinary skill in the art and will vary to some extent onthe context in which it is used. If there are uses of the term which arenot clear to person of ordinary skill in the art given the context inwhich it is used, “about” will mean up to about ±10% of the particularterm.

As used herein, a “therapeutically effective” or “therapeuticallyacceptable” amount refers to an amount that will elicit atherapeutically useful response in a subject and includes an additionalamount or overage of active ingredient deemed necessary in theformulation to provide the desired amount upon administration. Thetherapeutically useful response can provide some alleviation,mitigation, and/or decrease in at least one clinical symptom in thesubject. Those skilled in the art will appreciate that thetherapeutically useful response need not be complete or curative, aslong as some benefit is provided to the subject. In some embodiments,the subject is a human.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, and/or inhibiting theprogress of a disease or disorder as described herein. In someembodiments, treatment can be administered after one or more symptomshave developed. In other embodiments, treatment can be administered inthe absence of symptoms. For example, treatment can be administered to asusceptible individual prior to the onset of symptoms (e.g., in light ofa history of symptoms and/or in light of genetic or other susceptibilityfactors). Treatment can also be continued after symptoms have resolved,for example to prevent or delay their recurrence.

As used herein, the term “immediate release” refers to release of atleast 70% of a drug in one hour (i.e., one hour post-administration).

As used herein, the terms “extended release” and “sustained release” canbe used interchangeably and refer to dosage forms or compositions thatare formulated to provide therapeutic drug concentrations over anextended period of time after administration, thereby allowing areduction in dosing frequency, as compared to a drug presented as animmediate release dosage form.

As used herein, the term “floating” is used in conjunction with a“floating gastroretentive dosage form”, which has a bulk density lessthan gastric fluids. Such dosage forms are “floating” in that theyremain buoyant in the gastric fluids of the stomach for a targetedperiod of time. The floating dosage form then is able to be retained inthe stomach, while releasing an active agent.

As used herein, the terms “floating lag time” and “lag time” refer tothe time between the addition of a dosage form to a medium and the timewhen the dosage form begins to float on the medium (e.g., in an in vitrosetting), or the time between the consumption of a dosage form by a userand the time when the dosage form begins to float on the surface of thegastric fluid (e.g., in an in vivo setting).

As used herein, the term “gastroretentive dosage form,” can be usedinterchangeably with the term “gastroretentive oral floating drugdelivery system”. These terms refer to modified release dosage formsproviding delayed gastric emptying as compared to food (e.g., retentionin the stomach beyond the retention of food).

The term “pyridostigmine,” as used herein, refers to the pyridostigmineas well as all pharmaceutically acceptable salts, esters, andfunctionally equivalent chemical compounds of pyridostigmine.

The terms “initial burst release” and/or “dose dumping,” as use herein,refer to an unintended initial spike in concentration of pyridostigminein extended release dosage forms.

The terms “reduced initial burst release,” and the like, as used herein,refer to in vitro release of from about 20% to about 35% of thepyridostigmine within two hours of dissolution in a dissolution medium,measured using USP Apparatus I (Custom Basket), at about 100 rpm andabout 37° C.

The terms “minimized initial burst release”, and the like, as usedherein, refer to in vitro release of not more than 20% of thepyridostigmine within two hours of dissolution in a dissolution medium,measured using USP Apparatus I (Custom Basket), at about 100 rpm andabout 37° C.

The terms “pore former” and the like, as used herein, refer towater-soluble polymers and/or water-soluble small molecules that willform pores or channels (i.e., behave as a channeling agent) in thefunctional coat/membrane, thereby creating a permeable functionalcoat/membrane. The term “pore former” includes molecules used to createa certain amount of diffusion through an insoluble (or sparinglysoluble) coating of a tablet, pellet, or particle to achieve an extendedrelease profile.

The term “simulated gastric fluid,” as used herein, refers to mediumthat is used to mimic the chemical environment of gastric medium invitro.

The term “gastric fluid,” as used herein, refers to medium occurring instomach of an individual.

The term “dissolution medium,” as used herein, refers to a biorelevantmedium mimicking gastric fluid conditions. In certain embodiments, themedium includes 50 mM of pH 4.5 acetate buffer; 50 mM of pH 4.5 acetatebuffer with 100 mM NaCl; pH 5.0 buffer with 150 mM NaCl; pH 2.0 mediumwith 100 mM NaCl; 0.01 N HCl; or a mixture of 150 mM NaCl, 30 mM sodiumacetate, and 17 mM acetic acid.

The terms “swellable,” “swelling,” and the like, as used herein withrespect to a polymer, refer to a polymer capable of imbibing fluid andswelling when in contact with a fluid environment.

The terms “expanding,” “expansion,” and the like, as used herein withrespect to a permeable elastic membrane, refer to stretching ordistention of a membrane due to the membrane elasticity, and an outwardpressure, e.g., gas pressure, on the membrane.

The term “permeable,” as used herein, refers to a membrane containingsparingly soluble polymers, or insoluble polymers, with or without apore former, that will allow particles and fluids to pass throughmembrane by diffusion. As used herein, the terms functional coat andpermeable membrane are used interchangeably.

The terms “wicking agent,” and “disintegrants,” as used interchangeablyherein, refer to a material(s) with the ability to draw and spread waterinto the core of the dosage form. Wicking agents help to increase thecontact surface area of the drug with the incoming aqueous fluid, whichhelps to enhance the rate of drug released from the dosage form. Wickingagents carry water to surfaces inside the core of the tablet to createchannels or a network of increased surface area.

The term “low viscosity hydroxypropyl methylcellulose/hypromellose,” asused herein, refers to hydroxypropyl methylcellulose/hypromellose 2208(“K” type) with a viscosity of between about 50 mPa·s and about 2,400mPa·s, and a weight average molecular weight of between about 150,000and about 300,000.

The term “high viscosity hydroxypropyl methylcellulose/hypromellose,” asused herein, refers to hydroxypropyl methylcellulose/hypromellose 2208(“K type) or hydroxypropyl methylcellulose/hypromellose 2910 (“E” type)with a viscosity of between about 2,500 mPa·s and about 300,000 mPa·s,and a weight average molecular weight of between about 350,000 and about1,500,000.

The term “dual-controlled release,” as used herein, refers to drugrelease from a membrane-controlled matrix (also referred to as amembrane-controlled matrix core or membrane-controlled core). The term“dual-controlled release” includes drug release that is controlled byboth the matrix and the membrane portions of the dosage form, e.g.,matrix-controlled and membrane-controlled release of pyridostigminebromide.

6.2. Pyridostigmine Dosage Forms

The disclosed subject matter provides for extended release compositionscontaining pyridostigmine. The presently disclosed subject matter alsoprovides for formulating the extended release compositions containingpyridostigmine into various dosage forms, such as, e.g., matrix tablets,gastroretentive tablets, and pellets. In certain embodiments, thepresent disclosure provides for dosage forms that contain an IR layercontaining pyridostigmine bromide to eliminate the lag time associatedwith the presence of an extended release component alone. In certainembodiments, the extended release dosage forms without an immediaterelease layer provide minimized initial burst release, and the extendedrelease dosage forms containing an immediate release layer providereduced initial burst release of the drug, compared to marketed extendedrelease pyridostigmine products. In certain embodiments, the extendedrelease dosage forms of the present disclosure are formulated tominimize the “dose dumping” drug release (also referred to herein as“minimized initial burst release”) during the first one to two hours ofdissolution, compared with the currently marketed ER pyridostigmineproducts. Such dose dumping is believed to be responsible for unwantedGI side effects experienced with the currently marketed ERpyridostigmine products. Thus, the extended release dosage forms of thedisclosure minimize the GI side effects, and provide and maintaintherapeutic plasma concentrations of pyridostigmine for a period of atleast about 14 hours. In certain embodiments, the extended releasepyridostigmine dosage forms of the disclosure provide residual plasmalevels of the drug in the morning, such that patients wake up feelingmore refreshed and more functional before taking the morning dose, ascompared with the currently marketed pyridostigmine products. In certainembodiments, the reduced initial drug concentration (e.g., reducedinitial burst release) is sufficient to provide a therapeutic effect andavoid GI side effects. In certain embodiments, the extended releasedosage forms of the disclosure either (1) contain an IR drug layercontaining pyridostigmine bromide or (2) are administered with an IRpyridostigmine dosage form, in order to eliminate the lag time.

In certain embodiments, the gastroretentive dosage forms of the presentdisclosure provide extended release of pyridostigmine bromide for up toabout 24 hours.

In certain embodiments, the gastroretentive dosage form comprisingpyridostigmine bromide of the present disclosure comprises an immediaterelease layer and an extended release component, wherein both theimmediate release layer and the extended release component containpyridostigmine bromide, and wherein the dosage form provides an extendedrelease, with reduced initial burst release, of pyridostigmine bromide,for at least about 14 hours.

The extended release compositions described herein comprisepyridostigmine and/or pharmaceutically acceptable salts thereof.Nonlimiting pharmaceutically acceptable salts include hydrochloride,hydrobromide, hydroiodide, bromide, sulfite, sulfate, bisulfate,nitrate, salicylate, citrate, tartrate, bitartrate, lactate, phosphate,malate, maleate, fumarate, succinate, acetate, and pamoate salts. Incertain embodiments, the pharmaceutically acceptable salt is bromide.

In certain embodiments, a pyridostigmine salt is present in amounts offrom about 50 mg to about 500 mg per dose, and any other range inbetween. In certain embodiments, a pyridostigmine salt can be present inamounts from about 60 mg to about 450 mg, 60 mg to about 400 mg, fromabout 60 mg to about 360 mg, from about 60 mg to about 300 mg, fromabout 60 mg to about 240 mg, from about 60 mg to about 180 mg, or fromabout 60 mg to about 120 mg per dose, and any other range in between. Incertain embodiments, a pyridostigmine salt can be present in an amountof about 80 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg,about 300 mg, about 350 mg, about 400 mg, or any intermediate valuestherein, per dose to provide a wide range of doses depending on thedisease severity. In certain embodiments, the pyridostigmine salt ispresent in an immediate release layer and an extended release component.In certain embodiments, the immediate release layer contains betweenabout 0 mg and about 60 mg of a pyridostigmine salt. In certainembodiments, the immediate release layer contains about 5 mg, about 10mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg,about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, or anyintermediate amounts therein, of a pyridostigmine salt. In certainembodiments, the extended release component contains between about 50 mgand about 400 mg of a pyridostigmine salt. In certain embodiments, theextended release component contains about 55 mg, about 60 mg, about 65mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg,about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg,about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg,about 325 mg, about 350 mg, about 375 mg, about 400 mg, or anyintermediate amounts therein, of a pyridostigmine salt. In certainembodiments, the compositions of the disclosure include the followingamounts of a pyridostigmine salt in the IR layer/ER component,respectively: about 30 mg/about 70 mg; about 20 mg/about 160 mg; about20 mg/about 180 mg; about 45 mg/about 155 mg; about 45 mg/about 205 mg;about 45 mg/about 255 mg; about 45 mg/about 305 mg; or about 45 mg/about355 mg. In certain embodiments, the compositions of the disclosureinclude the following amounts of a pyridostigmine salt in the IRlayer/ER component, respectively: about 10 mg/about 50 mg; about 15mg/about 85 mg; about 30 mg/about 70 mg; about 37.5 mg/about 212.5 mg;or about 52.5 mg/about 297.5 mg.

In certain embodiments, the pyridostigmine salt is pyridostigminebromide. In certain embodiments, pyridostigmine bromide is present inamounts of from about 50 mg to about 500 mg per dose, and any otherrange in between. In certain embodiments, pyridostigmine bromide can bepresent in amounts from about 60 mg to about 450 mg, 60 mg to about 400mg, from about 60 mg to about 360 mg, from about 60 mg to about 300 mg,from about 60 mg to about 240 mg, from about 60 mg to about 180 mg, orfrom about 60 mg to about 120 mg per dose, and any other range inbetween. In certain embodiments, pyridostigmine bromide can be presentin an amount of about 80 mg, about 100 mg, about 150 mg, about 200 mg,about 250 mg, about 300 mg, about 350 mg, about 400 mg, or anyintermediate values therein, per dose to provide a wide range of dosesdepending on the disease severity. In certain embodiments, thepyridostigmine bromide is present in an immediate release layer and anextended release component. In certain embodiments, the immediaterelease layer contains between about 0 mg and about 60 mg ofpyridostigmine bromide. In certain embodiments, the immediate releaselayer contains about 5 mg, about 10 mg, about 15 mg, about 20 mg, about25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg,about 55 mg, about 60 mg, or any intermediate amounts therein, ofpyridostigmine bromide. In certain embodiments, the extended releasecomponent contains between about 50 mg and about 400 mg ofpyridostigmine bromide. In certain embodiments, the extended releasecomponent contains about 55 mg, about 60 mg, about 65 mg, about 70 mg,about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about350 mg, about 375 mg, about 400 mg, or any intermediate amounts therein,of pyridostigmine bromide. In certain embodiments, the compositions ofthe disclosure include the following amounts of pyridostigmine bromidein the IR layer/ER component, respectively: about 30 mg/about 70 mg;about 20 mg/about 160 mg; about 20 mg/about 180 mg; about 45 mg/about155 mg; about 45 mg/about 205 mg; about 45 mg/about 255 mg; about 45mg/about 305 mg; or about 45 mg/about 355 mg. In certain embodiments,the compositions of the disclosure include the following amounts ofpyridostigmine bromide in the IR layer/ER component, respectively: about10 mg/about 50 mg; about 15 mg/about 85 mg; about 30 mg/about 70 mg;about 37.5 mg/about 212.5 mg; or about 52.5 mg/about 297.5 mg.

In certain embodiments, the compositions of the disclosure can beadministered QD as a single dosage unit. In certain embodiments, thecompositions of the disclosure can be administered QD as multiple dosageunits (e.g., two, three, or four dosage units).

In certain embodiments, the present disclosure provide for ahorizontally compressed, oval-shaped gastroretentive tablet dosage formcontaining a long axis and a short axis, wherein the long axis isbetween about 12 mm and about 22 mm, and the short axis is between about8 mm and about 11 mm, and wherein the tablet, when in contact with mediasimulating gastric conditions, floats in about 30 minutes or less, andexpands in about 60 minutes or less to a size that prevents its passagethrough a pyloric sphincter of a human.

In certain embodiments, the tablets maintain their GRS attributes offlotation and expansion for at least about 14 hours, at least about 16hours, at least about 18 hours, or at least about 24 hours, or anyintermediate time periods therein. In certain embodiments, the tabletsin a fully expanded state can withstand compression forces of about 10 Nuntil about 14 hours, and after about 20 hours the matrix core can besqueezed even with a compression force less than 5 N.

6.2.1. Matrix Tablets

In certain embodiments, the extended release pyridostigmine compositionsof the disclosure can be formulated as a matrix tablet comprising a ratecontrolling matrix core coated with a rate controlling functionalcoat/membrane, e.g., membrane-controlled matrix.

In certain embodiments, the matrix tablet of the disclosure can comprisea rate-controlling matrix core coated with a rate-controlling functionalcoat/membrane, e.g., a membrane-controlled matrix core. In certainembodiments, the matrix tablet of the disclosure can comprise arate-controlling matrix core, a seal coat over the matrix core, afunctional coat/membrane over the seal coat, a second seal coat over thefunctional coat, an immediate release layer over the seal coat, and anover coat/aesthetic coat over the immediate release layer. In certainembodiments, the matrix tablet can exclude an immediate release layer.In particular embodiments, in the absence of an immediate release layer,the over coat is the outermost coat.

In certain embodiments, the matrix core can be made by dry granulation.In certain embodiments, the matrix core can comprise pyridostigminebromide, and at least one water-insoluble pH-independent lipophilicmaterial. In certain embodiments, the matrix tablets can comprisepyridostigmine bromide and at least one swellable water-solublehydrophilic polymer. As matrix tablets can be susceptible to stickingand mottling due to the hygroscopic nature of pyridostigmine bromide,the matrix tablets of the present disclosure can include an over coat toreduce the exposure of pyridostigmine bromide to moisture. In certainembodiments, the over coat can be the outermost coat. In certainembodiments, the release rate of pyridostigmine bromide from the matrixtablets of the disclosure can be controlled by varying the amount oflipophilic material in the matrix core and the composition of thefunctional coat over the matrix core. In certain embodiments, therelease rate of pyridostigmine bromide from the compositions of thedisclosure can be controlled by adjusting the coating level of thefunctional coat over the matrix core. In certain embodiments,water-insoluble material in the matrix core reduces drug dissolution andprovides extended release of the drug, without initial burst release,for extended periods of time. In certain embodiments, thewater-insoluble material can enhance compressibility of the composition.In certain embodiments, the water-insoluble material can include, but isnot limited to, ethyl acrylate and methyl methacrylate copolymer(EUIDRAGIT® NE, EUDRAGIT® NM), ammonio methacrylate copolymer (EUDRAGIT®RL 100, EUDRAGIT® RS 100, EUDRAGIT® RL PO, EUDRAGIT® RS PO), carnaubawax, stearic acid, ethylcellulose (ETHOCEL™), cellulose acetate, andsilicon dioxide.

In certain embodiments, the matrix core can further comprise glidants,lubricants, compression aids, and fillers.

In certain embodiments, the disclosed matrix tablets can comprise one ormore glidant materials to improve the flow of granules, and help tominimize the dosage form from weight variations. In certain embodiments,the glidants include, but are not limited to, silicon dioxide (SYLOID®244FP), fumed silica (CAB-O-SIL®), talc, kaolin, or any combinationsthereof.

In certain embodiments, the disclosed matrix tablets can comprisediluents and/or fillers. In certain embodiments, the diluents and/orfillers include, but are not limited to, lactose monohydrate USP,anhydrous lactose USP, directly compressible starches, hydrolyzedstarches, pregelatinized starch, microcrystalline cellulose, silicifiedmicrocrystalline cellulose, carboxymethylcellulose and other cellulosepolymers, sucrose and sucrose-based materials, dextrose, dibasic calciumphosphate anhydrous, dibasic calcium phosphate dihydrate, tricalciumphosphate, calcium sulfate dihydrate, and other alkaline inorganicsalts, sugar alcohols such as mannitol (e.g., PARTECK® M200, MANNOGEM®XL), sorbitol, and xylitol, and confectioner's sugar.

In certain embodiments, diluents and/or fillers can be used ascompression aids. In certain embodiments, diluents and/or fillers thatcan be used as compression aids include, but are not limited to,microcrystalline cellulose, silicified microcrystalline cellulose, andmannitol (e.g., PARTECK® M200, MANNOGEM® XL). In certain embodiments,the diluent and/or filler can be used in an amount of less than about30% w/w of the tablet core. In certain embodiments, the diluent and/orfiller can be present in an amount of from about 10% to about 40% w/w ofthe tablet. In certain embodiments, the diluent and/or filler can bepresent in an amount of less than about 25% w/w, less than about 24%w/w, less than about 23% w/w, less than about 22% w/w, less than about21% w/w, less than about 20% w/w, less than about 15% w/w, less thanabout 10% w/w, less than about 5% w/w, or less than about 2.5% w/w ofthe total weight of the tablet core, or intermediate values thereof.

In certain embodiments, the matrix core can also include one or morelubricants. Lubricants are hydrophobic substances that decrease frictionat the interface between a tablet's surface and the die wall duringejection and reduce wear on punches and dies. Lubricants enhance productflow by reducing interparticulate friction. In certain embodiments, theone or more lubricants can be, but are not limited to, magnesiumstearate, stearic acid, calcium soaps, zinc stearate, polyoxyethylenemonostearate, solid polyethylene glycols, calcium silicate, colloidalsilicon dioxide, hydrogenated vegetable oils and fats, glycerylmonostearate, palmitic acid, talc, carnauba wax, mineral oil,polyethylene glycol, glyceryl palmitostearate, sodium benzoate, sodiumstearyl fumarate, and any combination thereof. In certain embodiments,the lubricant is magnesium stearate. In certain embodiments, thelubricant can be present in an amount of from about 0.1% w/w to about 5%w/w based on the total weight of the matrix core. In certainembodiments, the lubricant can be present in an amount of less thanabout 4% w/w, less than about 3% w/w, less than about 2% w/w, less thanabout 1.5% w/w, less than about 1.4% w/w, less than about 1.3% w/w, lessthan about 1.2% w/w, less than about 1.1% w/w, or less than about 1.0%w/w based on the total weight of the matrix core.

In certain embodiments, the drug release can be controlled by amatrix-controlled membrane, e.g., a matrix core and functional coat overthe matrix core. In certain embodiments, the drug release can becontrolled by the functional coat/membrane. In certain embodiments, thematrix core can contain rate controlling water-insoluble materialselected from a group comprising, but not limited to, ethyl acrylate andmethyl methacrylate copolymer (EUDRAGIT® NE, EUDRAGIT® NM), ammoniomethacrylate copolymer (EUDRAGIT® RL 100, EUDRAGIT® RS 100, EUDRAGIT® RLPO, EUDRAGIT® RS PO), carnauba wax, stearic acid, ethylcellulose(ETHOCEL™), cellulose acetate, and silicon dioxide. In certainembodiments, the matrix core can contain rate-controlling swellablewater-soluble hydrophilic polymer selected from the group comprising,but not limited to, hydroxypropyl methylcellulose (BENECEL™ K4M PH DC),hydroxypropyl methylcellulose (METHOCEL K100 Premium LVCR/LVDC), apolyethylene oxide polymer, a carbomer, sodium alginate, or mixturesthereof. In certain embodiments, the swellable water-soluble hydrophilicpolymer can be BENECEL™ K4M PH DC. In certain embodiments, thewater-soluble hydrophilic polymer can be METHOCEL K100 PremiumLVCR/LVDC. In certain embodiments, the water-soluble hydrophilic polymercan be a mixture of METHOCEL K100 Premium LVCR/LVDC and BENECEL™ K4M PHDC.

In certain embodiments, the functional coat can contain rate controllingwater-insoluble material. In certain embodiments, the rate controllingpolymers in the functional coat can comprise, but are not limited to,ethyl acrylate and methyl methacrylate copolymer (EUDRAGIT® NE,EUDRAGIT® NM), ammonio methacrylate copolymer (EUDRAGIT® RL 100,EUDRAGIT® RS 100, EUDRAGIT® RL 30D, EUDRAGIT® RS 30D, EUDRAGIT® RL PO,EUDRAGIT® RS PO), carnauba wax, stearic acid, ethylcellulose (ETHOCEL™),cellulose acetate, and polyvinyl acetate dispersion (KOLLICOAT® SR). Incertain embodiments, the functional coat can further comprise awater-soluble pore former. In certain embodiments, the water-solublepore former can include, but is not limited to, polyethylene glycol (PEG400, PEG 1000, PEG 1450, PEG 3350), hydroxypropyl cellulose, polyvinylpyrolidone (PVP), KOLLIDON® 30, KOLLICOAT® IR, mannitol, andmethylcellulose (METHOCEL™ E3, METHOCEL™ E5, METHOCEL™ E6).

In certain embodiments, the matrix core and the functional coat over thematrix core can include stearic acid, ethylcellulose, cellulose acetate,and/or silicon dioxide to control the release of pyridostigmine bromide.In certain embodiments, the matrix core can be at least partiallycovered with the functional coat. In certain embodiments, the functionalcoat can completely surround the matrix core.

In certain embodiments, the matrix tablet can further include a sealcoat between the matrix core and the functional coat. In certainembodiments, the seal coat can cover at least a portion of the matrixcore. In certain embodiments, the seal coat can comprise a nonionicwater-soluble polymer. In certain embodiments, the nonionicwater-soluble polymer can be selected from the group consisting of apolyvinyl alcohol-based polymer, methyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, andmixtures thereof.

In certain embodiments, the matrix tablet can further include an overcoat. In certain embodiments, the over coat can cover at least a portionof the functional coat. In certain embodiments, the over coat cancompletely cover the functional coat. In certain embodiments, the overcoat can comprise one or more water-soluble hydrophilic polymersselected from the group consisting of water-soluble polymer selectedfrom a group consisting of a polyvinyl alcohol-based polymer (e.g.,Opadry® II), methyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, and mixtures thereof. Incertain embodiments, the water-soluble hydrophilic polymers in the overcoat can include polyvinyl alcohol and polyethylene glycol, e.g.,Opadry® White.

In certain embodiments, the matrix core can be further coated with animmediate release drug layer comprising pyridostigmine bromide. Incertain embodiments, the dosage form comprises a matrix core, afunctional coat covering at least a portion of the matrix core, a sealcoat covering at least a portion of the functional coat, an IR druglayer covering at least a portion of the seal coat, and an overcoat/aesthetic coat covering at least a portion of the IR drug layer.

In certain embodiments, the matrix tablets can comprise a matrix coreand a functional coat. In certain embodiments, the matrix core cancomprise one or more of pyridostigmine bromide, stearic acid, carnaubawax, ethylcellulose, silicon dioxide, fumed silica, mannitol, magnesiumstearate and combinations thereof. In certain embodiments, the matrixcore can comprise from about 100 mg to about 250 mg, from about 150 mgto about 200 mg, or about 180 mg of pyridostigmine bromide. In certainembodiments, the matrix core can further optionally comprise from about20 mg to about 200 mg, from about 50 mg to about 180, or about 90 mg ofstearic acid. In certain embodiments, the matrix core can furtheroptionally comprise from about 50 mg to about 200 mg, or from about 80mg to about 160 mg of carnauba wax. In certain embodiments, the matrixcore can further optionally comprise from about 50 mg to about 150 mg,or about 100 mg of ethylcellulose. In certain embodiments, the matrixcore can further optionally comprise from about 20 mg to about 250 mg,from about from about 50 mg to about 200 mg, or about 180 mg of silicondioxide. In certain embodiments, the matrix core can further optionallycomprise from about 5 mg to about 40 mg, from about 10 mg to about 25mg, or about 20 mg of fumed silica. In certain embodiments, the matrixcore can further comprise from about 50 mg to about 200 mg, from about75 mg to about 150 mg, or about 100 mg of mannitol. In certainembodiments, the matrix core can further comprise from about 1 mg toabout 10 mg, from about 3 mg to about 7 mg, or about 5 mg of magnesiumstearate. In certain embodiments, the matrix tablet comprises afunctional coat. In certain embodiments, the functional coat cancomprise one or more of cellulose acetate, polyethylene glycol,methylcellulose, and combinations thereof. In certain embodiments, thefunctional coat can comprise from about 10 mg to about 70 mg, from about30 mg to about 65 mg, or from about 40 mg to about 50 mg of celluloseacetate. In certain embodiments, the functional coat can furthercomprise from about 1 mg to about 10 mg, from about 1.5 mg to about 7mg, or from about 2 mg to about 5 mg of polyethylene glycol. In certainembodiments, the functional coat can further comprise from about 2 mg toabout 10 mg, from about 3 mg to about 7 mg, or from about 3 mg to about5 mg of methylcellulose.

6.2.2. Gastroretentive Tablets

In embodiments, the extended release pyridostigmine compositions can beformulated as gastroretentive tablets that provide a constant reservoirfor continuous absorption of pyridostigmine in the proximalgastrointestinal tract and provide constant levels of pyridostigmineover extended periods of time. The sustained release profile with fewerfluctuations in the plasma concentration is expected to fulfill an unmetneed by reducing the frequency of dosing while providing better controlof symptoms and improved tolerability (e.g., decreased side effects,including unwanted GI side effects) compared to currently marketedpyridostigmine products. The gastroretentive compositions (e.g.,tablets) of the disclosure are particularly suitable for long-termtreatment of mild to moderate MG, and as an adjunct therapy in patientswho are also receiving steroids and immunotherapy. In certainembodiments, the gastroretentive tablets of the disclosure can providegastric retention and continuous release of pyridostigmine, withoutinitial dose dumping of pyridostigmine, for at least about 14 hours,e.g., about 24 hours.

In certain embodiments, the gastroretentive tablets of the disclosurecan comprise an expanding core and a permeable elastic membranesurrounding the core, wherein the core and the membrane together canprovide controlled extended release, with minimized (e.g., eliminated)or reduced dose dumping/initial burst release, of pyridostigmine bromidefor at least about 14 hours.

In certain embodiments, the gastroretentive tablets of the disclosurecan comprise an immediate release layer and an extended releasecomponent. The immediate release layer can comprise pyridostigminebromide, and the extended release component can comprise a core coatedwith a permeable elastic membrane. In certain embodiments, the immediaterelease layer can provide a drug plasma concentration that is sufficientto overcome the lag time in pyridostigmine release seen withoutapplication of an IR layer, and sufficient to provide instanttherapeutic effects, with possible reduced or eliminated GI sideeffects, and the extended release component can provide controlledextended release of the drug for a period of at least about 14 hours.

In certain embodiments, the gastroretentive tablets of the disclosure,when in contact with simulated gastric medium, can expand in about 60minutes or less to a size that would prevent its passage through apyloric sphincter. In certain embodiments, the gastroretentive tabletsof the disclosure can float in about 10 minutes or less, expand in about60 minutes or less to a size that prevents passage through the pyloricsphincter, and provide extended release of pyridostigmine for at leastabout 14 hours, e.g., about 24 hours.

6.2.2.1 Permeable Membrane/Functional Coat

The gastroretentive compositions (e.g., tablets) of the disclosure caninclude a rapidly expanding membrane surrounding a hydrophilic core. Incertain embodiments, the membrane can be a water-insoluble, permeableelastic membrane surrounding the core. The permeable membrane can allowthe flow of gastric fluid into the composition, which initiates gasgeneration from gas-generating agents, and the membrane flexibility canallow for rapid expansion and immediate flotation of the composition. Incertain embodiments, the membrane can comprise a plasticizer and atleast one ammonium polymethacrylate copolymer.

The ammonium polymethacrylate copolymer provides permeability of themembrane and the plasticizer improves elasticity and mechanical strengthof the membrane. The plasticizer can provide elasticity to the membrane,ensuring that the membrane does not rupture upon expanding and that thegastroretentive drug delivery system provides the desiredcharacteristics for drug release, hydrodynamic balance, and mechanicalstrength to withstand variations in pH and shear in the stomach duringfed and fasted conditions. In certain embodiments, as dissolution of theactive agent in the core proceeds, the plasticizer can leach out of themembrane. In certain embodiments, leaching of the plasticizer can makethe membrane brittle, such that the membrane does not remain intact andthe dosage form can break into pieces by the end of drug release.Hydrophilic plasticizers suitable for the disclosure include, but arenot limited to, glycerin, polyethylene glycols, polyethylene glycolmonomethyl ether, propylene glycol, sorbitol sorbitan solution, andmixtures thereof. Hydrophobic plasticizers suitable for the disclosureinclude, but are not limited to, acetyl tributyl citrate, acetyltriethyl citrate, castor oil, diacetylated monoglycerides, dibutylsebacate, diethyl phthalate, triacetin, tributyl citrate, triethylcitrate, gelucire 39/01, gelucire 43/01, and mixtures thereof. Incertain embodiments, the plasticizers include various polyethyleneglycols, glycerin, and/or triethyl citrate. In certain embodiments, theplasticizer is triethyl citrate.

In certain embodiments of the disclosure, the permeable elastic membranecan comprise two (or more) water-insoluble polymers: at least one ofEUDRAGIT® RL 30D (copolymer dispersion of ethyl acrylate, methylmethacrylate, and methacrylic acid ester with quaternary ammoniumgroups, 1:2:0.2) and EUDRAGIT® RS 30D (copolymer dispersion of ethylacrylate, methyl methacrylate, and methacrylic acid ester withquaternary ammonium groups, 1:2:0.1) to improve permeability; and atleast one of KOLLICOAT® SR 30D (dispersion of polyvinyl acetate andpolyvinyl pyrolidone), EUDRAGIT® NE 30D (copolymer dispersion of ethylacrylate, methyl methacrylate), and EUDRAGIT® NM 30D (copolymerdispersion of ethyl acrylate, methyl methacrylate), to improvemechanical strength (tensile strength). The membrane can further includehydrophilic polymer and, optionally, water-soluble nonionic polymer thatact as a pore former, to modify its elasticity, permeability, andtensile strength.

In certain embodiments, the permeable elastic membrane can providedesired characteristics for drug release and tensile strength towithstand peristalsis and mechanical contractility of the stomach(shear). The combination of a water-soluble hydrophilic polymer in thecore, and the unique permeable elastic membrane formed over the tabletcore by the coating of a homogeneous dispersion of at least one ofEUDRAGIT® RL 30D and EUDRAGIT® RS 30D (collectively “dispersions ofammonium salts of polymethacrylate copolymers”) to improve permeability,and at least one of KOLLICOAT® SR 30D, EUDRAGIT® NE 30D, and EUDRAGIT®NM 30D (collectively “neutral polymethacrylate copolymer dispersions”)to improve mechanical strength (tensile strength), can provide thedesired extended drug release while maintaining the integrity of thecore in an expanded state, thus extending the gastric residence time andpreventing the dosage form from being emptied from the stomach untilsubstantial or complete release of the drug, usually after a prolongedperiod.

In certain embodiments, the water-insoluble polymers in the permeableelastic membrane can comprise at least one of EUDRAGIT® RL PO and/orEUDRAGIT® RS PO (i.e., ammonium polymethacrylate copolymers in powderform). In certain embodiments, the permeable elastic membrane can beformed over the core by coating the core with a solution of EUDRAGIT® RLPO (copolymer of ethyl acrylate, methyl methacrylate, andtrimethylammonioethyl methacrylate chloride (1:2:0.2) with a glasstransition temperature (T_(g)) of 63) and/or EUDRAGIT® RS PO (copolymerof ethyl acrylate, methyl methacrylate, and trimethylammonioethylmethacrylate chloride (1:2:0.1) with a glass transition temperature(T_(g)) of 65), a plasticizer, and talc.

In certain embodiments, the membrane can include a water-insolublepolymer, a plasticizer, and at least one pore former comprising awater-soluble nonionic polymer. In certain embodiments, the pore formersand plasticizers can modify membrane elasticity, permeability, andtensile strength. In certain embodiments, the membrane can exclude anypore former. In certain embodiments, examples of insoluble permeablecomponents of the permeable elastic membrane include, but are notlimited to, copolymers of ethyl acrylate, methyl methacrylate, andtrimethylammonioethyl methacrylate chlorides (e.g., EUDRAGIT® RL 30D orEUDRAGIT® RS 30D, EUDRAGIT® RS PO, EUDRAGIT® RL PO); cellulose acetatephthalate; ethyl cellulose; and hypromellose acetate succinate.

In certain embodiments, examples of insoluble components of thepermeable elastic membrane that provide elasticity to the membraneinclude, but are not limited to, copolymers of ethyl acrylate and methylmethacrylate (e.g., EUDRAGIT® NE 30D, EUDRAGIT® NM 30D), polyvinylacetates (e.g., KOLLICOAT® SR 30D), thermoplastic polyurethanes,ethylene-vinyl acetate, and polydimethyl siloxane.

In certain embodiments, the permeable elastic membrane can be a coatingof a solution of EUDRAGIT® RL PO and/or EUDRAGIT® RS PO. In certainembodiments, the core can be coated with a solution of EUDRAGIT® RL POand/or EUDRAGIT® RS PO in acetone and water mixture.

In certain embodiments, the coating dispersion can include at least oneof EUDRAGIT® RL PO and EUDRAGIT® RS PO (collectively “solutions ofammonium polymethacrylate copolymer”) to improve permeability, and atleast one plasticizer to improve mechanical strength (tensile strength).In certain embodiments, powder forms of EUDRAGIT®, e.g., EUDRAGIT® RL POand EUDRAGIT® RS PO, are preferred over EUDRAGIT® dispersions, e.g.,EUDRAGIT® RS 30D and EUDRAGIT® RL 30D.

In certain embodiments, the permeability of the permeable elasticmembrane can be adjusted to provide a floating lag time of less thanabout 10 minutes and floating time of about 1 hour to about 24 hours. Incertain embodiments, the gastroretentive pyridostigmine tablets of thedisclosure can comprise a membrane containing ammonium polymethacrylatecopolymer, e.g., EUDRAGIT® RL PO or EUDRAGIT® RS PO, and can exhibit afloating lag time of about 30 minutes or less and floating time of about1 hour to about 24 hours. In certain embodiments, the ammoniumpolymethacrylate copolymer can be present in an amount of between about70% and about 95% w/w of the membrane composition to provide desiredpermeability of the membrane. In certain embodiments, plasticizer can bepresent in an amount of between about 5 wt % and about 25 wt %, betweenabout 10 wt % and about 20 wt %, between about 10 wt % and about 15 wt%, and any intermediate ranges there in, of the membrane composition toprovide desired tensile strength, and elasticity for rapid expansion ofthe membrane. In certain embodiments, the plasticizer is present in anamount of at least about 10 wt %, at least about 11 wt %, at least about12 wt %, at least about 13 wt %, at least about 14 wt %, at least about15 wt %, at least about 16 wt %, at least about 17 wt %, at least about18 wt %, at least about 19 wt %, at least about 20 wt %, at least about21 wt %, at least about 22 wt %, at least about 23 wt %, at least about24 wt %, and at least about 25 wt % of the membrane composition.

In certain embodiments, the membrane can further include an anti-tackingagent selected from the group consisting of talc, colloidal silicondioxide, magnesium trisilicate, powdered cellulose, starch, and tribasiccalcium phosphate. In certain embodiments, the anti-tacking agent can becolloidal silicon dioxide and/or talc. In certain embodiments, theanti-tacking agent can be present in an amount of about 5 wt % to about30 wt % of the membrane composition. In certain embodiments, theanti-tacking agent is present in an amount of about 5 wt %, about 10 wt%, about 15 wt %, about 20 wt %, about 25 wt %, about 30 wt %, or anyintermediate values therein, by weight of the membrane composition.

In certain embodiments, the membrane can expand the dosage form in about30 minutes to a size that prevents its passage through the pyloricsphincter, and the hydrophilic core, surrounded by the membrane, canswell with imbibition and absorption of fluid and assist the membrane inproviding an extended release of the drug. In certain embodiments, themembrane can be highly elastic and flexible due to the presence of atleast one plasticizer and/or a copolymer of ethyl acrylate and methylmethacrylate, and can expand rapidly with an outward pressure on themembrane from the generated CO₂ gas.

In certain embodiments, the membrane can provide an extended release ofthe drug for at least about fourteen hours, e.g., about twenty-fourhours.

6.2.2.2 Core

In certain embodiments, the core can comprise pyridostigmine or apharmaceutically acceptable salt thereof (e.g., pyridostigmine bromide),an acid, a gas-generating agent, a disintegrant/wicking agent, and atleast one swellable water-soluble hydrophilic polymer.

In certain embodiments, the swellable water-soluble hydrophilic polymerin the core can comprise a high viscosity hydroxypropylmethylcellulose/hypromellose with a viscosity of between about 2,500mPa·s and about 300,000 mPa·s, and a weight average molecular weight ofbetween about 350,000 and about 1,500,000 (e.g., BENECEL™ K4M PH DC witha viscosity of between about 2,700 mPa·s and 5,040 mPa·s); a lowviscosity hydroxypropyl methylcellulose/hypromellose with a viscosity ofbetween about 50 mPa·s and about 2,400 mPa·s, and a weight averagemolecular weight of between about 150,000 and about 300,000 (e.g.,METHOCEL K100 Premium LVCR/LVDC with a viscosity of between about 80mPa·s and 120 mPa·s), a polyethylene oxide polymer, a carbomer, sodiumalginate, or mixtures thereof. In certain embodiments, the water-solublehydrophilic polymer can be hypromellose 2208 with a viscosity of betweenabout 2,700 mPa·s and 5,040 mPa·s (BENECEL™ K4M PH DC). In certainembodiments, the swellable water-soluble hydrophilic polymer can behypromellose 2208 with a viscosity of between about 80 mPa·s and 120mPa·s (METHOCEL K100 Premium LVCR/LVDC). In certain embodiments, theswellable water-soluble hydrophilic polymer can be a mixture of two ormore hypromelloses with different viscosities, e.g., METHOCEL K100Premium LVCR/LVDC and BENECEL™ K4M PH DC. In certain embodiments, thelow viscosity hypromellose has a viscosity of between about 80 mPa·s andabout 120 mPa·s, between about 200 mPa·s and about 300 mPa·s, betweenabout 562 mPa·s and about 1050 mPa·s, or between about 1,125 mPa·s andabout 2,100 mPa·s. In certain embodiments, the low viscosityhypromellose has a weight average molecular weight of about 164,000,about 200,000, about 250,000, or about 300,000. In certain embodiments,the high viscosity hypromellose has a viscosity of between about 2,700mPa·s and about 5,040 mPa·s, between about 13,500 mPa·s and about 25,200mPa·s, between about 26,250 mPa·s and about 49,000 mPa·s, between about75,000 mPa·s and about 140,000 mPa·s, or between about 150,000 mPa·s andabout 280,000 mPa·s. In certain embodiments, the high viscosityhypromellose has a weight average molecular weight of about 400,000,about 575,000, about 675,000, about 1,000,000, or about 1,200,000. Incertain embodiments, the water-soluble hydrophilic polymer is present inan amount of between about 5 wt % and about 35 wt %, based on the totalweight of the core. In certain embodiments, the hypromellose 2208, witha viscosity of between about 2,700 mPa·s and about 5,040 mPa·s, ispresent in an amount of between about 5 wt % and about 35 wt %, based onthe total weight of the core. In certain embodiments, the hypromellose2208, with a viscosity of between about 2,700 mPa·s and about 5,040mPa·s, is present in an amount of about 5 wt %, about 10 wt %, about 15wt %, about 20 wt %, about 25 wt %, about 30 wt %, or about 35 wt %,based on the total weight of the core. In certain embodiments, dosageforms comprising hypromellose 2208, with a viscosity of between about2,700 mPa·s and about 5,040 mPa·s, present in an amount of about 30 wt%, based on the total weight of the core, provide extended release ofpyridostigmine bromide for at least about 14 hours. In certainembodiments, the dosage form comprises a low viscosity hypromellose 2208with a viscosity of between about 80 mPa·s and about 120 mPa·s (e.g.,METHOCEL K100 Premium LVCR/LVDC). In certain embodiments, METHOCEL K100Premium LVCR/LVDC is present in an amount of about 5 wt %, about 10 wt%, about 15 wt %, about 20 wt %, about 25 wt %, about 30 wt %, or about35 wt %, based on the total weight of the core. In certain embodiments,the mixture of METHOCEL K100 Premium LVCR/LVDC and BENECEL™ K4M PH DC inthe dosage form provides extended release of pyridostigmine bromide forabout 14 hours or more. In certain embodiments, the presence ofhypromellose 2208 in an amount of between about 20% w/w and about 35%w/w of the core, helps in providing extended release of the drug for atleast about 14 hours. In certain embodiments, the presence of METHOCELK100 Premium LVCR/LVDC in the mixture of two or more hypromellose 2208aids in the complete emptying of the dosage form at the end of the drugrelease period.

In certain embodiments, the core comprises gas-generating agents thatcan generate CO₂ on interaction with acid. Examples of gas-generatingagents that can be used in the compositions of the present disclosureinclude, but are not limited to, all organic and inorganic strong andweak bases, e.g., carbonate and bicarbonate salts of alkali and alkalineearth metals, that can interact with stomach acid for in situ gasgeneration. In certain embodiments, the gas-generating agent can besodium bicarbonate, sodium carbonate, magnesium carbonate, and/orcalcium carbonate. In certain embodiments, a mixture of calciumcarbonate and sodium bicarbonate can provide desired sustained releaseof CO₂. In certain embodiments, the gas-generating agent can be presentin an amount of at about 5 wt % to about 50 wt % of core. In certainembodiments, the gas-generating agent can be present in an amount ofabout 5 wt %, about 10 wt %, about 15 wt %, about 20 wt %, about 25 wt%, about 30 wt %, about 35 wt %, about 40 wt %, about 45 wt %, about 50wt %, or any intermediate values therein, based on the total weight ofthe core.

In certain embodiments, the core can comprise an acid to achieve rapidfloating and expansion of the tablet, regardless of the gastric pH. Incertain embodiments, the acids include, but are not limited to, succinicacid, citric acid, acetic acid, malic acid, fumaric acid, stearic acid,tartaric acid, boric acid, benzoic acid, or mixtures thereof. In certainembodiments, the acid can be succinic acid. In certain embodiments, theacid can be present in an amount of between 0 wt % and about 20 wt % ofthe core. In certain embodiments, the acid can be present in an amountof about 0.5 wt %, about 1 wt %, about 2 wt %, about 3 wt %, about 4 wt%, about 5 wt %, about 6 wt %, about 7 wt %, about 8 wt %, about 9 wt %,about 10 wt %, about 12.5 wt %, about 15 wt %, about 20 wt %, or anyintermediate values therein, based on the total weight of the core.

In certain embodiments, the acid is succinic acid and the gas-generatingagent is a mixture of sodium bicarbonate and calcium carbonate. Incertain embodiments, the gastroretentive dosage forms of the disclosureinclude equimolar amounts of acid and each of sodium bicarbonate andcalcium carbonate (e.g., equimolar amounts of succinic acid and sodiumbicarbonate, and equimolar amounts of succinic acid and calciumcarbonate).

In certain embodiments, the core can comprise a wickingagent/disintegrant selected from a group comprising, but not limited to,croscarmellose sodium; sodium starch glycolate; low-substitutedhydroxypropyl cellulose; a mixture of 90% mannitol, 5% crospovidone, and5% polyvinyl acetate (LUDIFLASH®); a coprocessed blend of mannitol,starch, crospovidone, croscarmellose sodium, colloidal silica, andsilica (PHARMABURST®); microcrystalline cellulose; alginic acid; andmixtures thereof. In certain embodiments, the wicking agent can becrospovidone. In certain embodiments, the wicking agent is present in anamount of about 5 wt % to about 25 wt % of the core. In certainembodiments, the wicking agent is present in amount of about 5 wt %,about 10 wt %, about 15 wt %, about 20 wt %, about 25 wt %, or anyintermediate values therein, based on the total weight of the core.

In certain embodiments, the core can further include at least onelubricant selected from the group comprising magnesium stearate,glyceryl monostearates, palmitic acid, talc, carnauba wax, calciumstearate sodium, sodium or magnesium lauryl sulfate, calcium soaps, zincstearate, polyoxyethylene monostearates, calcium silicate, silicondioxide, hydrogenated vegetable oils and fats, stearic acid, and anycombinations thereof. In certain embodiments, the lubricant is magnesiumstearate. In certain embodiments, the lubricant can be present in anamount of about 0.1 wt % to about 2 wt % of the core. In certainembodiments, the lubricant can be present in an amount of about 0.5 wt%, about 0.6 wt %, about 0.7 wt %, about 0.8 wt %, about 0.9 wt %, about1.0 wt %, about 1.1 wt %, about 1.2 wt %, about 1.3 wt %, about 1.4 wt%, about 1.5 wt %, about 1.6 wt %, about 1.7 wt %, about 1.8 wt %, about1.9 wt %, about 2.0 wt %, or any intermediate values therein, based onthe total weight of the core.

In certain embodiments, the core can include at least one glidantselected from the group comprising talc, colloidal silicon dioxide,magnesium trisilicate, powdered cellulose, starch, and tribasic calciumphosphate. In certain embodiments, the glidant can be colloidal silicondioxide. In certain embodiments, the glidant can be present in an amountof about 0.1 wt % to about 2 wt % based on the total weight of the core.In certain embodiments, the glidant can be present in an amount of about0.1 wt %, about 0.2 wt %, about 0.3 wt %, about 0.4 wt %, about 0.5 wt%, about 0.6 wt %, about 0.7 wt %, about 0.8 wt %, about 0.9 wt %, about1 wt %, about 1.5 wt %, about 2 wt %, or any intermediate valuestherein, based on the total weight of the core.

In certain embodiments, the core can further comprise afiller/compression aid. In certain embodiments, mannitol can be used asa filler/compression aid. In certain embodiments, mannitol can be usedas an osmotic agent. In certain embodiments, mannitol can be present inan amount of about 1 wt % to about 40 wt % based on the total weight ofthe core.

In certain embodiments, the core can further comprise at least one colorpigment. In certain embodiments, the core can include at least onepigment comprising iron oxide or lake-based colors. In certainembodiments, the pigment can be a lake-based color. In certainembodiments, the pigment can be an iron oxide pigment, e.g., oxidepigment black or Red blend. In certain embodiments, the pigment can bepresent in an amount of about 0.5 wt % to about 2 wt % based on thetotal weight of the core.

6.2.2.3 Immediate Release Drug Layer

In certain embodiments, the gastroretentive pyridostigmine compositions(e.g., tablets) of the disclosure can include an immediate release layerand an extended release component to provide a biphasic release ofpyridostigmine or a pharmaceutically acceptable salt thereof. In certainembodiments, the immediate release layer can cover at least a portion ofthe functional coat/permeable membrane. In certain embodiments, theimmediate release layer can comprise pyridostigmine or apharmaceutically acceptable salt thereof and a binder.

In certain embodiments, the binder(s) can be selected from the groupconsisting of, but not limited to, povidone K 90, hypromellose, starch,acacia, gellan gum, low viscosity hydroxypropyl cellulose,methylcellulose, sodium methylcellulose, polyvinyl alcohol, polyvinylacetates (e.g., KOLLICOAT® SR), polyethylene oxide (e.g., POLYOX®),polyethylene glycol, alginates, and pegylated polyvinyl alcohol. Incertain embodiments, the binder can be hydroxypropyl cellulose. Incertain embodiments, the binders can be present in an amount of about0.5 wt % to about 30 wt % of the amount of drug in the immediate releasedrug layer. In certain embodiments, the binders can be present in anamount of about 0.5 wt %, about 0.6 wt %, about 0.7 wt %, about 0.8 wt%, about 0.9 wt %, about 1 wt %, about 2 wt %, about 3 wt %, about 4 wt%, about 5 wt %, about 6 wt %, about 7 wt %, about 8 wt %, about 9 wt %,about 10 wt %, about 15 wt %, about 20 wt %, about 25 wt %, about 30 wt%, or any intermediates values therein, of the amount of drug in theimmediate release drug layer.

6.2.2.4 Additional Coats

In certain embodiments, the gastroretentive tablets of the disclosurefurther can include a seal coat between the core and the permeableelastic membrane and/or between the permeable elastic membrane and theimmediate release drug layer. In certain embodiments, the seal coat cancover at least a portion of the membrane. In certain embodiments, theseal coat can comprise one or more water-soluble hydrophilic polymersselected from the group consisting of a polyvinyl alcohol-based polymer(OPADRY® white, OPADRY® clear), methyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, andmixtures thereof. In certain embodiments, the seal coat can comprisehydroxypropyl cellulose. In certain embodiments, the seal coat can bepresent in an amount of about 0.5 wt % to about 5 wt % of the uncoatedcore, membrane-coated core, or core with drug layer. In certainembodiments, the seal coat can be present in an amount of about 0.5 wt%, about 1 wt %, about 1.5 wt %, about 2 wt %, about 2.5 wt %, about 3wt %, about 3.5 wt %, about 4 wt %, about 4.5 wt %, about 5 wt %, or anyintermediate values therein, of the uncoated core, membrane-coated core,or core with drug layer.

In certain embodiments, the gastroretentive tablets of the disclosurefurther includes an over coat/aesthetic coat. In certain embodiments,the over coat covers at least a portion of the permeable elasticmembrane (in a composition without an IR drug layer) or a portion ofdrug layer (in a composition with an IR drug layer). In certainembodiments, the over coat can completely cover the permeable elasticmembrane or the IR drug layer. In certain embodiments, the over coat canbe the outermost coat. In certain embodiments, the over coat cancomprise one or more water-soluble hydrophilic polymers selected fromthe group consisting of methylcellulose, hydroxymethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methylcellulose, and polyvinylalcohol-based OPADRY® white.

In certain embodiments, the gastroretentive tablets of the disclosurecan include at least one laser-drilled orifice/hole that passes throughthe permeable elastic membrane/functional coat and seal coat. In certainembodiments, the gastroretentive dosage forms of the disclosure includemultiple laser-drilled orifices/holes. In certain embodiments, thegastroretentive dosage forms of the disclosure do not includelaser-drilled holes in the IR drug layer and the over coat (i.e.,laser-drilled holes do not pass through these layers).

6.2.2.5 Compositions

In certain embodiments, the present disclosure provide for agastroretentive dosage form comprising an immediate release layercontaining pyridostigmine bromide, and an extended release component,wherein the extended release component comprises a core comprisingpyridostigmine bromide, an acid, a gas-generating agent, and awater-soluble hydrophilic polymer that swells via imbibition of gastricfluid, and a permeable elastic membrane surrounding the core andcomprising a plasticizer, and a copolymer based on ethyl acrylate,methyl methacrylate, and trimethylammonioethyl methacrylate chloride,and wherein the dosage form provides an extended release, with reducedinitial burst release, of pyridostigmine bromide, for at least about 14hours. In certain embodiments, the core of the dosage form of thepresent disclosure includes a wicking agent selected from the groupconsisting of crospovidone; croscarmellose sodium; sodium starchglycolate; low-substituted hydroxypropyl cellulose; a mixture ofmannitol, crospovidone, and polyvinyl acetate; a coprocessed blend ofmannitol, starch, crospovidone, croscarmellose sodium, colloidal silica,and silica; microcrystalline cellulose; alginic acid; and mixturesthereof. In certain other embodiments, the core of the dosage formcomprises crospovidone as a wicking agent. In certain embodiments, thedosage form of the present disclosure comprises a water-solublehydrophilic polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropyl cellulose, methyl cellulose, apolyethylene oxide polymer, a carbomer, sodium alginate, and mixturesthereof. In particular embodiments, the water-soluble hydrophilicpolymer is hydroxypropyl methylcellulose. In certain other embodiments,the water-soluble hydrophilic polymer is methyl cellulose. In certainother embodiments, the water-soluble hydrophilic polymer is a mixture ofhydroxypropyl methylcellulose with an average molecular weight ofgreater than or equal to 164,000 and less than 400,000, andhydroxypropyl methylcellulose with an average molecular weight ofbetween about 400,000 and about 1,200,000. In certain embodiments, thedosage form of the present disclosure comprises a gas-generating agentselected from the group consisting of NaHCO₃, CaCO₃, and a mixturethereof. In certain embodiments, the gas-generating agent is a mixtureof NaHCO₃ and CaCO₃. In certain embodiments, the dosage form of thepresent disclosure comprises a plasticizer selected from the groupconsisting of triethyl citrate, triacetin, polyethylene glycol,propylene glycol, dibutyl sebacate, and mixtures thereof. In particularembodiments, the plasticizer is triethyl citrate. In certainembodiments, the permeable elastic membrane of the dosage form of thepresent disclosure is at least partially covered by the immediaterelease drug layer. In certain embodiments, the present disclosureprovides for a dosage form that further includes a seal coat between theimmediate release drug layer and the permeable elastic membrane. Incertain embodiments, the seal coat of the dosage form or the presentdisclosure comprises a water-soluble polymer selected from the groupconsisting of a polyvinyl alcohol-based polymer, methyl cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, or a mixture thereof. In certain embodiments, thedosage form of the present disclosure further includes an over coat overthe immediate release drug layer. In particular embodiments, the overcoat comprises a water-soluble polymer selected from a group consistingof a polyvinyl alcohol-based polymer, methyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, or amixture thereof.

In certain embodiments, the present disclosure provides for an extendedrelease gastroretentive pyridostigmine tablet comprising an immediaterelease layer containing pyridostigmine bromide, and an extended releasecomponent, wherein the extended release component comprises a corecomprising pyridostigmine bromide, an acid, a gas-generating agent, anda water-soluble hydrophilic polymer that swells via imbibition ofgastric fluid; and a permeable elastic membrane, surrounding the core,comprising a plasticizer, and a copolymer based on ethyl acrylate,methyl methacrylate, and trimethylammonioethyl methacrylate chloride,and wherein the tablet is suitable for once daily administration and isadministered as a single tablet/day. In certain embodiments, the tabletof present disclosure comprises 100 mg, 200 mg, 250 mg, 300 mg, or 350mg of pyridostigmine bromide.

In certain embodiments, the water-soluble hydrophilic polymer of thetablet of the present disclosure is selected from the group consistingof hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, a polyethylene oxide polymer, a carbomer, sodium alginate,and mixtures thereof. In certain embodiments, the gas-generating agentof the tablet of the present disclosure comprises NaHCO₃, CaCO₃, or amixture thereof. In certain embodiments, the plasticizer of the tabletof the present disclosure is selected from the group consisting oftriethyl citrate, triacetin, polyethylene glycol, propylene glycol,dibutyl sebacate, and mixtures thereof. In certain embodiments, thetablet of the present disclosure further includes a wicking agentselected from the group consisting of crospovidone; croscarmellosesodium; sodium starch glycolate; low-substituted hydroxypropylcellulose; a mixture of mannitol, crospovidone, and polyvinyl acetate; acoprocessed blend of mannitol, starch, crospovidone, croscarmellosesodium, colloidal silica, and silica; microcrystalline cellulose;alginic acid; and mixtures thereof. In certain embodiments, thepermeable elastic membrane of the tablet of the present disclosure is atleast partially covered by the immediate release drug layer. In certainembodiments, the tablet of the present disclosure further includes aseal coat between the immediate release drug layer and the permeableelastic membrane. In certain embodiments, the seal coat of the tablet ofthe present disclosure comprises a water soluble polymer selected fromthe group consisting of a polyvinyl alcohol-based polymer, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, or a mixture thereof. In certainembodiments, the present disclosure provides for a tablet that furtherincludes an over coat over the immediate release drug layer. In certainembodiments, the overcoat of the tablets of the present disclosurecomprises a water-soluble polymer selected from a group consisting of apolyvinyl alcohol-based polymer, methyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, andmixtures thereof.

In certain embodiments, the pyridostigmine bromide gastroretentivetablets can comprise a core, a functional coat, and an overcoat. Incertain embodiment, the core of the pyridostigmine bromidegastroretentive tablets can comprise one or more of pyridostigminebromide, succinic acid, sodium bicarbonate, calcium carbonate,crospovidone, mannitol, hydroxypropyl methylcellulose, methylcellulose,fumed silica, magnesium stearate, and combinations thereof. In certainembodiments, the core of the pyridostigmine bromide gastroretentivetablets can comprise from about 100 mg to about 250 mg, from about 150mg to about 200 mg, or about 180 mg of pyridostigmine bromide. Incertain embodiments, the core can further comprise from about 20 mg toabout 100 mg, from about 40 mg to about 80 mg, or from about 50 mg toabout 60 mg of succinic acid. In certain embodiments, the core canfurther comprise from about 20 mg to about 80 mg, from about 30 mg toabout 65 mg, or from about 45 mg to about 55 mg of sodium bicarbonate.In certain embodiments, the core can further comprise from about 40 mgto about 200 mg, from about 50 mg to about 150 mg, or from about 60 mgto about 130 mg of calcium carbonate. In certain embodiments, the corecan further comprise from about 50 mg to about 200 mg, or about 100 mgof crospovidone. In certain embodiments, the core can further comprisefrom about 100 mg to about 300 mg, from about 150 mg to about 250 mg, orabout 230 mg of mannitol. In certain embodiments, the core can furtheroptionally comprise from about 50 mg to about 350 mg, from about 100 mgto about 300 mg, or about 200 mg of hydroxypropyl methylcellulose withan average molecular weight of about 400,000. In certain embodiments,the core can further optionally comprise from about 150 mg to about 350mg, or from about 200 mg to about 300 mg of hydroxypropylmethylcellulose with an average molecular weight of about 164,000. Incertain embodiments, the core can further comprise from about 1 mg toabout 10 mg, from about 2 mg to about 7 mg, or about 4 mg of fumedsilica. In certain embodiments, the core can further comprise from about1 mg to about 15 mg, from about 5 mg to about 10 mg, or about 8 mg ofmagnesium stearate. In certain embodiments, the pyridostigmine bromidegastroretentive tablets can further comprise a seal coat. In certainembodiments, the seal coat can comprise one or more of triethyl citrate,talc, hydroxypropyl cellulose, and combinations thereof. In certainembodiments, the pyridostigmine bromide gastroretentive tablets canfurther comprise a functional coat over the seal coat. In certainembodiments, the functional coat of the pyridostigmine bromidegastroretentive tablets can comprise from about 100 mg to about 200 mg,from about 125 mg to about 175 mg, or from about 145 mg to about 150 mgof ammonio methacrylate copolymer. In certain embodiments, thefunctional coat of the pyridostigmine bromide gastroretentive tabletscan further comprise from about 10 mg to about 50 mg, from about 15 mgto about 30 mg, or from about 20 mg to about 25 mg of triethyl citrate.In certain embodiments, the functional coat of the pyridostigminebromide gastroretentive tablets can further comprise from about 10 mg toabout 50 mg, from about 20 mg to about 40 mg, or from about 25 mg toabout 35 mg of talc. In certain embodiments, the pyridostigmine bromidegastroretentive tablets can comprise an over coat. In certainembodiments, the over coat can comprise from about 5 mg to about 30 mg,from about 10 mg to about 20 mg, or about 15 mg of polyvinylalcohol-based polymer.

In certain embodiments, the pyridostigmine bromide gastroretentivetablets can comprise a core, and a functional coat. In certainembodiment, the core of the pyridostigmine bromide gastroretentivetablets can comprise one or more of pyridostigmine bromide, succinicacid, sodium bicarbonate, calcium carbonate, crospovidone, mannitol,hydroxypropyl methylcellulose, methylcellulose, fumed silica, magnesiumstearate, and combinations thereof. In certain embodiments, the core ofthe pyridostigmine bromide gastroretentive tablets can comprise fromabout 50 mg to about 200 mg, from about 100 mg to about 150 mg, or about135 mg of pyridostigmine bromide. In certain embodiments, the core canfurther comprise from about 40 mg to about 150 mg, from about 60 mg toabout 100 mg, or from about 75 mg to about 85 mg of succinic acid. Incertain embodiments, the core can further comprise from about 20 mg toabout 80 mg, from about 30 mg to about 65 mg, or from about 45 mg toabout 55 mg of sodium bicarbonate. In certain embodiments, the core canfurther comprise from about 10 mg to about 100 mg, from about 25 mg toabout 75 mg, or from about 60 mg to 70 mg of calcium carbonate.

In certain embodiments, the core can further comprise from about 50 mgto about 200 mg, or about 100 mg of crospovidone. In certainembodiments, the core can further comprise from about 100 mg to about300 mg, from about 150 mg to about 275 mg, or from about 200 mg to about255 mg of mannitol. In certain embodiments, the core can furtheroptionally comprise from about 50 mg to about 250 mg, from about 100 mgto about 20 mg, or about 150 mg of hydroxypropyl methylcellulose with anaverage molecular weight of about 400,000. In certain embodiments, thecore can further comprise from about 100 mg to about 450 mg, from about150 mg to about 350 mg, or from about 150 mg to about 300 mg ofhydroxypropyl methylcellulose with an average molecular weight of about164,000. In certain embodiments, the core can further comprise fromabout 1 mg to about 10 mg, from about 2 mg to about 8 mg, or from about3 mg to about 5 mg of fumed silica. In certain embodiments, the core canfurther comprise from about 1 mg to about 15 mg, from about 5 mg toabout 10 mg, or about 8 mg of magnesium stearate. In certainembodiments, the pyridostigmine bromide gastroretentive tablets canfurther comprise a functional coat. In certain embodiments, thefunctional coat can comprise ammonio methacrylate copolymer, triethylcitrate, talc, and combinations thereof. In certain embodiments, thefunctional coat of the pyridostigmine bromide gastroretentive tabletscan comprise from about 100 mg to about 250 mg, from about 125 mg toabout 200 mg, or from about 145 mg to about 190 mg of ammoniomethacrylate copolymer. In certain embodiments, the functional coat ofthe pyridostigmine bromide gastroretentive tablets can further comprisefrom about 10 mg to about 50 mg, from about 15 mg to about 35 mg, fromabout 20 mg to about 30 mg of triethyl citrate. In certain embodiments,the functional coat of the pyridostigmine bromide gastroretentivetablets can further comprise from about 10 mg to about 50 mg, from about20 mg to about 40 mg, or from about 25 mg to about 30 mg of talc.

In certain embodiments, the pyridostigmine bromide gastroretentivetablets can comprise a core, and a functional coat. In certainembodiments, the core of the pyridostigmine bromide gastroretentivetablets can comprise one or more of pyridostigmine bromide, succinicacid, sodium bicarbonate, calcium carbonate, crospovidone, mannitol,hydroxypropyl methylcellulose, fumed silica, magnesium stearate, andcombinations thereof. In certain embodiments, the core of thepyridostigmine bromide gastroretentive tablets can comprise from about50 mg to about 200 mg, from about 100 mg to about 150 mg, or about 135mg of pyridostigmine bromide. In certain embodiments, the core canfurther comprise from about 50 mg to about 150 mg, from about 80 mg toabout 30 mg, or about 125 mg of succinic acid. In certain embodiments,the core can further comprise from about 30 mg to about 100 mg, or fromabout 50 mg to about 75 mg of sodium bicarbonate. In certainembodiments, the core can further comprise from about 25 mg to about 150mg, from about 50 mg to about 100 mg, or from about 60 mg to about 75 mgof calcium carbonate. In certain embodiments, the core can furthercomprise from about 100 mg to about 300 mg, from about 150 mg to about250 mg, or about 200 mg of crospovidone. In certain embodiments, thecore can further comprise from about 10 mg to about 200 mg, from about25 mg to about 50 mg, from about 100 mg to about 200 mg, or from about150 mg to about 175 mg of mannitol. In certain embodiments, the core canfurther optionally comprise from about 25 mg to about 150 mg, from about50 mg to about 125 mg, or about 100 mg of hydroxypropyl methylcellulosewith an average molecular weight of about 400,000. In certainembodiments, the core can further comprise from about 50 mg to about 450mg, or from about 100 mg to about 200 mg of hydroxypropylmethylcellulose with an average molecular weight of about 164,000. Incertain embodiments, the core can further comprise from about 1 mg toabout 10 mg, from about 2 mg to about 8 mg, or from about 3 mg to about

5 mg of fumed silica. In certain embodiments, the core can furthercomprise from about 1 mg to about 15 mg, from about 5 mg to about 10 mg,or about 8 mg of magnesium stearate. In certain embodiments, thepyridostigmine bromide gastroretentive tablets can further comprise afunctional coat. In certain embodiments, the functional coat cancomprise one or more of ammonio methacrylate copolymer, triethylcitrate, talc, and combinations thereof. In certain embodiments, thefunctional coat of the pyridostigmine bromide gastroretentive tabletscan comprise from about 50 mg to about 250 mg, from about 100 mg toabout 200 mg, or from about 125 mg to about 150 mg of ammoniomethacrylate copolymer. In certain embodiments, the functional coat ofthe pyridostigmine bromide gastroretentive tablets can further comprisefrom about 10 mg to about 40 mg, from about 15 mg to about 30 mg, orfrom about 20 mg to about 25 mg of triethyl citrate. In certainembodiments, the functional coat of the pyridostigmine bromidegastroretentive tablets can further comprise from about 10 mg to about50 mg, from about 20 mg to about 40 mg, or from about 25 mg to about 35mg of talc.

In certain embodiments, the pyridostigmine bromide gastroretentivetablets can comprise a core, and a functional coat. In certainembodiments, the core of the pyridostigmine bromide gastroretentivetablets can comprise one or more of pyridostigmine bromide, succinicacid, sodium bicarbonate, calcium carbonate, crospovidone, mannitol,hydroxypropyl methylcellulose fumed silica, magnesium stearate, andcombinations thereof. In certain embodiments, the core of thepyridostigmine bromide gastroretentive tablets can comprise from about100 mg to about 250 mg, from about 150 mg to about 200 mg, or about 180mg of pyridostigmine bromide. In certain embodiments, the core canfurther comprise from about 50 mg to about 150 mg, from about 80 mg toabout 30 mg, or about 125 mg of succinic acid. In certain embodiments,the core can further comprise from about 30 mg to about 100 mg, or fromabout 50 mg to about 75 mg of sodium bicarbonate. In certainembodiments, the core can further comprise from about 25 mg to about 150mg, from about 70 mg to about 125 mg, or about 100 mg of calciumcarbonate. In certain embodiments, the core can further comprise fromabout 100 mg to about 300 mg, from about 150 mg to about 250 mg, orabout 200 mg of crospovidone. In certain embodiments, the core canfurther comprise from about 50 mg to about 200 mg, from about 75 mg toabout 150 mg, or from about 100 mg to about 125 mg of mannitol. Incertain embodiments, the core can further optionally comprise from about25 mg to about 150 mg, from about 50 mg to about 125 mg, or about 100 mgof hydroxypropyl methylcellulose with an average molecular weight ofabout 400,000. In certain embodiments, the core can further comprisefrom about 50 mg to about 300 mg, or from about 100 mg to about 200 mgof hydroxypropyl methylcellulose with an average molecular weight ofabout 164,000. In certain embodiments, the core can further comprisefrom about 1 mg to about 10 mg, from about 2 mg to about 8 mg, or fromabout 3 mg to about 5 mg of fumed silica. In certain embodiments, thecore can further comprise from about 1 mg to about 15 mg, from about 5mg to about 10 mg, or about 8 mg of magnesium stearate. In certainembodiments, the pyridostigmine bromide gastroretentive tablets canfurther comprise a functional coat. In certain embodiments, thefunctional coat can comprise one or more of ammonio methacrylatecopolymer, triethyl citrate, talc, and combinations thereof. In certainembodiments, the functional coat of the pyridostigmine bromidegastroretentive tablets can comprise from about 50 mg to about 200 mg,from about 75 mg to about 150 mg, or from about 100 mg to about 125 mgof ammonio methacrylate copolymer. In certain embodiments, thefunctional coat of the pyridostigmine bromide gastroretentive tabletscan further comprise from about 10 mg to about 40 mg, from about 15 mgto about 30 mg, or from about 20 mg to about 25 mg of triethyl citrate.In certain embodiments, the functional coat of the pyridostigminebromide gastroretentive tablets can further comprise from about 10 mg toabout 50 mg, from about 15 mg to about 40 mg, or from about 20 mg toabout 30 mg of talc.

In certain embodiments, the pyridostigmine bromide gastroretentivetablets can comprise a core, and a functional coat. In certainembodiments, the core of the pyridostigmine bromide gastroretentivetablets can comprise one or more of pyridostigmine bromide, succinicacid, sodium bicarbonate, calcium carbonate, crospovidone, mannitol,hydroxypropyl methylcellulose, fumed silica, magnesium stearate, andcombinations thereof. In certain embodiments, the core of thepyridostigmine bromide gastroretentive tablets can comprise from about150 mg to about 400 mg, from about 200 mg to about 450 mg, or from about250 to about 310 mg of pyridostigmine bromide. In certain embodiments,the core can further comprise from about 25 mg to about 125 mg, fromabout 50 mg to about 100 mg, or from about 75 mg to about 90 mg ofsuccinic acid. In certain embodiments, the core can further comprisefrom about 30 mg to about 100 mg, or from about 50 mg to about 75 mg ofsodium bicarbonate. In certain embodiments, the core can furthercomprise from about 20 mg to about 100 mg, from about 40 mg to about 80mg, or from about 60 mg to about 75 mg of calcium carbonate. In certainembodiments, the core can further comprise from about 50 mg to about 150mg, from about 75 mg to about 125 mg, or about 100 mg of crospovidone.In certain embodiments, the core can further comprise from about 25 mgto about 175 mg, from about 50 mg to about 150 mg, or from about 70 mgto about 125 mg of mannitol. In certain embodiments, the core canfurther optionally comprise from about 50 mg to about 200 mg, from about100 mg to about 175 mg, or about 150 mg of hydroxypropyl methylcellulosewith an average molecular weight of about 400,000. In certainembodiments, the core can further comprise from about 50 mg to about 200mg, from about 100 mg to about 175 mg, or about 150 mg of hydroxypropylmethylcellulose with an average molecular weight of about 164,000. Incertain embodiment, the core can further comprise from about 1 mg toabout 20 mg, from about 5 mg to about 15 mg, or about 10 mg of fumedsilica. In certain embodiment, the core can further comprise from about5 mg to about 20 mg, from about 10 mg to about 15 mg, or about 12 mg ofmagnesium stearate. In certain embodiments, the pyridostigmine bromidegastroretentive tablets can further comprise a functional coat. Incertain embodiments, the functional coat can comprise one or more ofammonio methacrylate copolymer, triethyl citrate, talc, and combinationsthereof. In certain embodiments, the functional coat of thepyridostigmine bromide gastroretentive tablets can comprise from about50 mg to about 200 mg, from about 75 mg to about 175 mg, or from about125 mg to about 150 mg of ammonio methacrylate copolymer. In certainembodiments, the functional coat of the pyridostigmine bromidegastroretentive tablets can further comprise from about 10 mg to about40 mg, from about 15 mg to about 30 mg, or from about 20 mg to about 25mg of triethyl citrate. In certain embodiments, the functional coat ofthe pyridostigmine bromide gastroretentive tablets can further comprisefrom about 10 mg to about 50 mg, from about 15 mg to about 40 mg, orfrom about 25 mg to about 30 mg of talc.

In certain embodiments, the pyridostigmine bromide gastroretentivetablets can comprise a core, a functional coat, a seal coat, a druglayer and an over coat. In certain embodiments, the core of thepyridostigmine bromide gastroretentive tablets can comprise one or moreof pyridostigmine bromide, succinic acid, sodium bicarbonate, calciumcarbonate, crospovidone, mannitol, hydroxypropyl methylcellulose, fumedsilica, magnesium stearate, oxide pigment black, and combinationsthereof. In certain embodiments, the core of the pyridostigmine bromidegastroretentive tablets can comprise from about 50 mg to about 200 mg,from about 100 mg to about 150 mg, or about 135 mg of pyridostigminebromide. In certain embodiments, the core can further comprise fromabout 25 mg to about 125 mg, from about 50 mg to about 100 mg, or fromabout 75 mg to about 90 mg of succinic acid. In certain embodiments, thecore can further comprise from about 30 mg to about 100 mg, from about50 mg to about 75 mg, or about 55 mg of sodium bicarbonate. In certainembodiments, the core can further comprise from about 20 mg to about 100mg, from about 40 mg to about 80 mg, or from about 60 mg to about 70 mgof calcium carbonate. In certain embodiments, the core can furthercomprise from about 50 mg to about 150 mg, from about 75 mg to about 125mg, or about 100 mg of crospovidone. In certain embodiments, the corecan further comprise from about 150 mg to about 400 mg, from about 200mg to about 350 mg, or from about 250 mg to about 300 mg of mannitol. Incertain embodiments, the core can further optionally comprise from about50 mg to about 200 mg, from about 100 mg to about 175 mg, or about 150mg of hydroxypropyl methylcellulose with an average molecular weight ofabout 400,000. In certain embodiments, the core can further comprisefrom about 50 mg to about 200 mg, from about 100 mg to about 175 mg, orabout 150 mg of hydroxypropyl methylcellulose with an average molecularweight of about 164,000. In certain embodiments, the core can furthercomprise from about 1 mg to about 20 mg, from about 5 mg to about 15 mg,or about 10 mg of fumed silica. In certain embodiments, the core canfurther comprise from about 5 mg to about 20 mg, from about 10 mg toabout 15 mg, or about 12 mg of magnesium stearate. In certainembodiments, the core can further optionally comprise from about 5 mg toabout 20 mg, or from about 10 mg to about 15 mg, or about 12 mg of oxidepigment black. In certain embodiments, the pyridostigmine bromidegastroretentive tablets can further comprise a functional coat. Incertain embodiments, the functional coat can comprise one or more ofammonio methacrylate copolymer, triethyl citrate, talc, and combinationsthereof. In certain embodiments, the functional coat of thepyridostigmine bromide gastroretentive tablets can comprise from about50 mg to about 200 mg, from about 75 mg to about 175 mg, or from about125 mg to about 150 mg of ammonio methacrylate copolymer. In certainembodiments, the functional coat of the pyridostigmine bromidegastroretentive tablets can further comprise from about 10 mg to about40 mg, from about 15 mg to about 30 mg, or from about 20 mg to about 25mg of triethyl citrate. In certain embodiments, the functional coat ofthe pyridostigmine bromide gastroretentive tablets can further comprisefrom about 10 mg to about 50 mg, from about 15 mg to about 40 mg, orfrom about 25 mg to about 30 mg of talc. In certain embodiments, thepyridostigmine bromide gastroretentive tablets can further comprise aseal coat. In certain embodiments the seal coat can comprise from about1 mg to about 20 mg, from about 5 mg to about 15 mg, or about 10 mg ofpolyvinyl alcohol-based polymer. In certain embodiments, thepyridostigmine bromide gastroretentive tablets can further comprise adrug layer. In certain embodiments, the drug layer can comprisepyridostigmine bromide, hydroxypropyl cellulose, and combinationsthereof. In certain embodiments, the drug layer can comprise from about10 mg to about 100 mg, from about 25 mg to about 75 mg, or from about 40mg to about 50 mg of pyridostigmine bromide. In certain embodiments, thedrug layer can comprise from about 1 mg to about 20 mg, from about 5 mgto about 15 mg, or from about 8 mg to about 12 mg of hydroxypropylcellulose. In certain embodiments, the pyridostigmine bromidegastroretentive tablets can further comprise an over coat. In certainembodiments, the over coat can comprise from about 20 mg to about 60 mg,from about 30 mg to about 50 mg, or about 40 mg of polyvinylalcohol-based polymer.

In certain embodiments, the pyridostigmine bromide gastroretentivetablets can comprise a core, and a functional coat. In certainembodiments, the core of the pyridostigmine bromide gastroretentivetablets can comprise one or more of pyridostigmine bromide, succinicacid, sodium bicarbonate, calcium carbonate, crospovidone, mannitol,hydroxypropyl methylcellulose, fumed silica, magnesium stearate, andcombinations thereof. In certain embodiments, the core of thepyridostigmine bromide gastroretentive tablets can comprise from about200 mg to about 400 mg, from about 250 mg to about 350 mg, or from about285 mg, to about 315 mg of pyridostigmine bromide. In certainembodiments, the core can further comprise from about 25 mg to about 125mg, from about 50 mg to about 100 mg, or from about 75 mg to about 90 mgof succinic acid. In certain embodiments, the core can further comprisefrom about 30 mg to about 100 mg, or from about 50 mg to about 75 mg ofsodium bicarbonate. In certain embodiments, the core can furthercomprise from about 20 mg to about 100 mg, from about 40 mg to about 80mg, or from about 60 mg to about 75 mg of calcium carbonate. In certainembodiments, the core can further comprise from about 50 mg to about 150mg, from about 75 mg to about 125 mg, or about 100 mg of crospovidone.In certain embodiments, the core can further optionally comprise fromabout 25 mg to about 175 mg, from about 50 mg to about 150 mg, fromabout 60 mg to about 100 mg, or from about 70 mg to about 85 mg ofmannitol. In certain embodiments, the core can further comprise fromabout 100 mg to about 300 mg, from about 125 mg to about 250 mg, or fromabout 150 mg to about 200 mg of hydroxypropyl methylcellulose with anaverage molecular weight of about 400,000. In certain embodiments, thecore can further comprise from about 100 mg to about 300 mg, from about125 mg to about 250 mg, or from about 150 mg to about 200 mg ofhydroxypropyl methylcellulose with an average molecular weight of about164,000. In certain embodiments, the core can further comprise fromabout 1 mg to about 20 mg, from about 5 mg to about 15 mg, or about 10mg of fumed silica. In certain embodiments, the core can furthercomprise from about 5 mg to about 20 mg, from about 10 mg to about 15mg, or about 12 mg of magnesium stearate. In certain embodiments, thepyridostigmine bromide gastroretentive tablets can further comprise afunctional coat. In certain embodiments, the functional coat cancomprise one or more of ammonio methacrylate copolymer, triethylcitrate, talc, and combinations thereof. In certain embodiments, thefunctional coat of the pyridostigmine bromide gastroretentive tabletscan comprise from about 50 mg to about 200 mg, from about 75 mg to about175 mg, or from about 125 mg to about 150 mg of ammonio methacrylatecopolymer. In certain embodiments, the functional coat of thepyridostigmine bromide gastroretentive tablets can further comprise fromabout 10 mg to about 40 mg, from about 15 mg to about 30 mg, or fromabout 20 mg to about 25 mg of triethyl citrate. In certain embodiments,the functional coat of the pyridostigmine bromide gastroretentivetablets can further comprise from about 10 mg to about 50 mg, from about15 mg to about 40 mg, or from about 25 mg to about 30 mg of talc.

In certain embodiments, the pyridostigmine bromide gastroretentivetablets can comprise a core, and a functional coat. In certainembodiments, the core of the pyridostigmine bromide gastroretentivetablets can comprise one or more of pyridostigmine bromide, succinicacid, sodium bicarbonate, calcium carbonate, crospovidone, mannitol,hydroxypropyl methylcellulose, fumed silica, magnesium stearate, andcombinations thereof. In certain embodiments, the core of thepyridostigmine bromide gastroretentive tablets can comprise from about100 mg to about 300 mg, from about 175 mg to about 275 mg, from about195 mg to about 210 mg, or from about 225 mg to about 260 mg ofpyridostigmine bromide. In certain embodiments, the core can furthercomprise from about 25 mg to about 125 mg, from about 50 mg to about 100mg, or from about 75 mg to about 90 mg of succinic acid. In certainembodiments, the core can further comprise from about 30 mg to about 100mg, or from about 50 mg to about 75 mg of sodium bicarbonate. In certainembodiments, the core can further comprise from about 20 mg to about 100mg, from about 40 mg to about 80 mg, or from about 60 mg to about 75 mgof calcium carbonate. In certain embodiments, the core can furthercomprise from about 50 mg to about 150 mg, from about 75 mg to about 125mg, or about 100 mg of crospovidone. In certain embodiments, the corecan further optionally comprise from about 50 mg to about 200 mg, fromabout 100 mg to about 175 mg, from about 120 mg to about 125 mg, or fromabout 120 mg to about 175 mg of mannitol. In certain embodiments, thecore can further comprise from about 100 mg to about 300 mg, from about125 mg to about 250 mg, or from about 150 mg to about 215 mg ofhydroxypropyl methylcellulose with an average molecular weight of about400,000. In certain embodiments, the core can further comprise fromabout 100 mg to about 300 mg, from about 125 mg to about 250 mg, or fromabout 150 mg to about 215 mg of hydroxypropyl methylcellulose with anaverage molecular weight of about 164,000. In certain embodiments, thecore can further comprise from about 1 mg to about 20 mg, from about 5mg to about 15 mg, or about 10 mg of fumed silica. In certainembodiments, the core can further comprise from about 5 mg to about 20mg, from about 10 mg to about 15 mg, or about 12 mg of magnesiumstearate. In certain embodiments, the pyridostigmine bromidegastroretentive tablets can further comprise a functional coat. Incertain embodiments, the functional coat can comprise one or more ofammonio methacrylate copolymer, triethyl citrate, talc, and combinationsthereof. In certain embodiments, the functional coat of thepyridostigmine bromide gastroretentive tablets can comprise from about50 mg to about 200 mg, from about 75 mg to about 175 mg, or from about125 mg to about 150 mg of ammonio methacrylate copolymer. In certainembodiments, the functional coat of the pyridostigmine bromidegastroretentive tablets can further comprise from about 10 mg to about40 mg, from about 15 mg to about 30 mg, or from about 20 mg to about 25mg of triethyl citrate. In certain embodiments, the functional coat ofthe pyridostigmine bromide gastroretentive tablets can further comprisefrom about 10 mg to about 50 mg, from about 15 mg to about 40 mg, orfrom about 25 mg to about 30 mg of talc.

In certain embodiments, the pyridostigmine bromide gastroretentivetablets can comprise a core, and a functional coat. In certainembodiments, the core of the pyridostigmine bromide gastroretentivetablets can comprise one or more of pyridostigmine bromide, succinicacid, sodium bicarbonate, calcium carbonate, crospovidone, mannitol,hydroxypropyl methylcellulose, fumed silica, magnesium stearate, andcombinations thereof. In certain embodiments, the core of thepyridostigmine bromide gastroretentive tablets can comprise from about50 mg to about 200 mg, from about 70 mg to about 170 mg, or from about100 mg to about 160 mg of pyridostigmine bromide. In certainembodiments, the core can further comprise from about 25 mg to about 125mg, from about 50 mg to about 100 mg, or from about 75 mg to about 90 mgof succinic acid. In certain embodiments, the core can further comprisefrom about 30 mg to about 100 mg, or from about 50 mg to about 75 mg ofsodium bicarbonate. In certain embodiments, the core can furthercomprise from about 20 mg to about 100 mg, from about 40 mg to about 80mg, or from about 60 mg to about 75 mg of calcium carbonate. In certainembodiments, the core can further comprise from about 50 mg to about 150mg, from about 75 mg to about 125 mg, or about 100 mg of crospovidone.In certain embodiments, the core can further optionally comprise fromabout 200 mg to about 350 mg, from about 210 mg to about 310 mg, or fromabout 220 to about 280 mg of mannitol. In certain embodiments, the corecan further comprise from about 100 mg to about 300 mg, from about 125mg to about 250 mg, or from about 150 mg to about 200 mg ofhydroxypropyl methylcellulose with an average molecular weight of about400,000. In certain embodiments, the core can further comprise fromabout 100 mg to about 300 mg, from about 125 mg to about 250 mg, or fromabout 150 mg to about 200 mg of hydroxypropyl methylcellulose with anaverage molecular weight of about 164,000. In certain embodiments, thecore can further comprise from about 1 mg to about 20 mg, from about 5mg to about 15 mg, or about 10 mg of fumed silica. In certainembodiments, the core can further comprise from about 5 mg to about 20mg, from about 10 mg to about 15 mg, or about 12 mg of magnesiumstearate. In certain embodiments, the pyridostigmine bromidegastroretentive tablets can further comprise a functional coat. Incertain embodiments, the functional coat can comprise one or more ofammonio methacrylate copolymer, triethyl citrate, talc, and combinationsthereof. In certain embodiments, the functional coat of thepyridostigmine bromide gastroretentive tablets can comprise from about50 mg to about 200 mg, from about 75 mg to about 175 mg, or from about125 mg to about 150 mg of ammonio methacrylate copolymer. In certainembodiments, the functional coat of the pyridostigmine bromidegastroretentive tablets can further comprise from about 10 mg to about40 mg, from about 15 mg to about 30 mg, or from about 20 mg to about 25mg of triethyl citrate. In certain embodiments, the functional coat ofthe pyridostigmine bromide gastroretentive tablets can further comprisefrom about 10 mg to about 50 mg, from about 15 mg to about 40 mg, orfrom about 25 mg to about 30 mg of talc.

In certain embodiments, the pyridostigmine bromide gastroretentivetablets can comprise a core, a functional coat, a seal coat, a druglayer, and an over coat. In certain embodiments, the core of thepyridostigmine bromide gastroretentive tablets can comprise one or moreof pyridostigmine bromide, succinic acid, sodium bicarbonate, calciumcarbonate, crospovidone, mannitol, hydroxypropyl methylcellulose, fumedsilica, magnesium stearate, and combinations thereof. In certainembodiments, the core of the pyridostigmine bromide gastroretentivetablets can comprise from about 50 mg, to about 200 mg, from about 100mg to about 150 mg, or about 135 mg of pyridostigmine bromide. Incertain embodiments, the core can further comprise from about 25 mg toabout 125 mg, from about 50 mg to about 100 mg, or from about 75 mg toabout 90 mg of succinic acid. In certain embodiments, the core canfurther comprise from about 30 mg to about 100 mg, from about 50 mg toabout 75 mg, or about 55 mg of sodium bicarbonate. In certainembodiments, the core can further comprise from about 20 mg to about 100mg, from about 40 mg to about 80 mg, or from about 60 mg to about 70 mgof calcium carbonate. In certain embodiments, the core can furthercomprise from about 50 mg to about 150 mg, from about 75 mg to about 125mg, or about 100 mg of crospovidone. In certain embodiments, the corecan further comprise from about 175 mg to about 300 mg, from about 200mg to about 275 mg, or from about 230 mg to 240 mg of mannitol. Incertain embodiments, the core can further optionally comprise from about50 mg to about 200 mg, from about 100 mg to about 175 mg, or about 150mg of hydroxypropyl methylcellulose with an average molecular weight ofabout 400,000. In certain embodiments, the core can further comprisefrom about 50 mg to about 200 mg, from about 100 mg to about 175 mg, orabout 150 mg of hydroxypropyl methylcellulose with an average molecularweight of about 164,000. In certain embodiments, the core can furthercomprise from about 1 mg to about 20 mg, from about 5 mg to about 15 mg,or about 10 mg of fumed silica. In certain embodiments, the core canfurther comprise from about 5 mg to about 20 mg, from about 10 mg toabout 15 mg, or about 12 mg of magnesium stearate. In certainembodiments, the core can further comprise from about 1 mg to about 20mg, from about 5 mg to about 15 mg, or from about 7 mg to about 12 mg ofoxide pigment black. In certain embodiments, the pyridostigmine bromidegastroretentive tablets can further comprise a functional coat. Incertain embodiments, the functional coat can comprise one or more ofammonio methacrylate copolymer, triethyl citrate, talc, and combinationsthereof. In certain embodiments, the functional coat of thepyridostigmine bromide gastroretentive tablets can comprise from about50 mg to about 200 mg, from about 75 mg to about 175 mg, or from about125 mg to about 150 mg of ammonio methacrylate copolymer. In certainembodiments, the functional coat of the pyridostigmine bromidegastroretentive tablets can further comprise from about 10 mg to about40 mg, from about 15 mg to about 30 mg, or from about 20 mg to about 25mg of triethyl citrate. In certain embodiments, the functional coat ofthe pyridostigmine bromide gastroretentive tablets can further comprisefrom about 10 mg to about 50 mg, from about 15 mg to about 40 mg, orfrom about 25 mg to about 30 mg of talc. In certain embodiments, thepyridostigmine bromide gastroretentive tablets can further comprise aseal coat. In certain embodiments, the seal coat can comprise polyvinylalcohol-based polymer. In certain embodiments, the seal coat cancomprise from about 1 mg to about 20 mg, from about 5 mg to about 15 mg,or about 10 mg of polyvinyl alcohol-based polymer. In certainembodiments, the pyridostigmine bromide gastroretentive tablets canfurther comprise a drug layer. In certain embodiments, the drug layercan comprise pyridostigmine bromide, and hydroxypropyl cellulose. Incertain embodiments, the drug layer can comprise from about 20 mg toabout 75 mg, from about 30 mg to about 60 mg, or from about 40 mg toabout 50 mg of pyridostigmine bromide. In certain embodiments, the druglayer can further comprise from about 1 mg to about 20 mg, from about 5mg to about 15 mg, or about 9 mg of hydroxypropyl cellulose. In certainembodiments, the pyridostigmine bromide gastroretentive tablets canfurther comprise an over coat. In certain embodiments, the overcoat cancomprise polyvinyl alcohol-based polymer. In certain embodiments, theover coat can comprise from about 10 mg to about 60 mg, from about 20 mgto about 50 mg, or about 40 mg of polyvinyl alcohol-based polymer.

In certain embodiments, the pyridostigmine bromide gastroretentivetablets can comprise a core, a functional coat, a seal coat, a druglayer, and an over coat. In certain embodiments, the core of thepyridostigmine bromide gastroretentive tablets can comprise one or moreof pyridostigmine bromide, succinic acid, sodium bicarbonate, calciumcarbonate, crospovidone, mannitol, hydroxypropyl methylcellulose, fumedsilica, magnesium stearate, and combinations thereof. In certainembodiments, the core of the pyridostigmine bromide gastroretentivetablets can comprise from about 25 mg to about 125 mg, from about 50 mgto about 100 mg, or about 75 mg of pyridostigmine bromide. In certainembodiments, the core can further comprise from about 25 mg to about 125mg, from about 50 mg to about 100 mg, or from about 75 mg to about 90 mgof succinic acid. In certain embodiments, the core can further comprisefrom about 30 mg to about 100 mg, from about 50 mg to about 75 mg, orabout 55 mg of sodium bicarbonate. In certain embodiments, the core canfurther comprise from about 20 mg to about 100 mg, from about 40 mg toabout 80 mg, or from about 60 mg to about 70 mg of calcium carbonate. Incertain embodiments, the core can further comprise from about 50 mg toabout 150 mg, from about 75 mg to about 125 mg, or about 100 mg ofcrospovidone. In certain embodiments, the core can further comprise fromabout 200 mg to about 350 mg, from about 250 mg to about 300 mg, or fromabout 270 mg to about 280 mg of mannitol. In certain embodiments, thecore can further optionally comprise from about 50 mg to about 200 mg,from about 100 mg to about 175 mg, or about 150 mg of hydroxypropylmethylcellulose with an average molecular weight of about 400,000. Incertain embodiments, the core can further comprise from about 50 mg toabout 200 mg, from about 100 mg to about 175 mg, or about 150 mg ofhydroxypropyl methylcellulose with an average molecular weight of about164,000. In certain embodiments, the core can further comprise fromabout 1 mg to about 20 mg, from about 5 mg to about 15 mg, or about 10mg of fumed silica. In certain embodiments, the core can furthercomprise from about 5 mg to about 20 mg, from about 10 mg to about 15mg, or about 12 mg of magnesium stearate. In certain embodiments, thecore can further comprise from about 1 mg to about 20 mg, from about 5mg to about 15 mg, or from about 7 mg to about 12 mg of oxide pigmentblack. In certain embodiments, the pyridostigmine bromidegastroretentive tablets can further comprise a functional coat. Incertain embodiments, the functional coat can comprise one or more ofammonio methacrylate copolymer, triethyl citrate, talc, and combinationsthereof. In certain embodiments, the functional coat of thepyridostigmine bromide gastroretentive tablets can comprise from about50 mg to about 200 mg, from about 75 mg to about 175 mg, or from about125 mg to about 150 mg of ammonio methacrylate copolymer. In certainembodiments, the functional coat of the pyridostigmine bromidegastroretentive tablets can further comprise from about 10 mg to about40 mg, from about 15 mg to about 30 mg, or from about 20 mg to about 25mg of triethyl citrate. In certain embodiments, the functional coat ofthe pyridostigmine bromide gastroretentive tablets can further comprisefrom about 10 mg to about 50 mg, from about 15 mg to about 40 mg, orfrom about 25 mg to about 30 mg of talc. In certain embodiments, thepyridostigmine bromide gastroretentive tablets can further comprise aseal coat. In certain embodiments, the seal coat can comprise polyvinylalcohol-based polymer. In certain embodiments, the seal coat cancomprise from about 1 mg to about 20 mg, from about 5 mg to about 15 mg,or about 10 mg of polyvinyl alcohol-based polymer. In certainembodiments, the pyridostigmine bromide gastroretentive tablets canfurther comprise a drug layer. In certain embodiments, the drug layercan comprise one of more of pyridostigmine bromide, and hydroxypropylcellulose and combinations thereof. In certain embodiments, the druglayer can comprise from about 10 mg to about 50 mg, from about 20 mg toabout 40 mg, or about 30 mg of pyridostigmine bromide. In certainembodiments, the drug layer can further comprise from about 1 mg toabout 20 mg, from about 5 mg to about 15 mg, or about 9 mg ofhydroxypropyl cellulose. In certain embodiments, the pyridostigminebromide gastroretentive tablets can further comprise an over coat. Incertain embodiments, the overcoat can comprise polyvinyl alcohol-basedpolymer. In certain embodiments, the over coat can comprise from about10 mg to about 60 mg, from about 20 mg to about 50 mg, or about 40 mg ofpolyvinyl alcohol-based polymer.

6.2.2.6 Features of Gastroretentive Dosage Forms

The gastroretentive tablets of the disclosure combine the following twokey attributes: gastric retention and continuous controlled drugdelivery for up to about 24 hours. In certain embodiments, thedisclosure provides gastroretentive tablets of pyridostigmine that aresuitable for providing stable pyridostigmine levels, with minimizedinitial burst release/dose dumping of the drug, for an extended periodof time. This is particularly desirable for myasthenia gravis (MG)patients, as the constant level of pyridostigmine has been shown toimprove therapeutic outcome and quality of life. Quality of life andcompliance are also enhanced with the reduction or elimination of dosedumping of pyridostigmine, as experienced with the currently marketed ERformulation, and the concomitant reduction in undesirable side effects.FIG. 18 compares pharmacokinetic data for gastroretentive Tablet 8 (T₁),pellet compositions T₂, and marketed pyridostigmine products, e.g.,MESTINON® tablets (60 mg/TID) (R₂) and MESTINON® TIMESPAN tablets (180mg/QD) (R₁). FIG. 18 demonstrates that bioavailability ofgastroretentive Tablet 8 (T₁) is comparable to MESTINON® (R₂) andMESTINON® TIMESPAN tablets (R₁) in the fed state. Pharmacokinetic datafrom FIG. 18 demonstrates that gastroretentive tablets of the disclosure(T1), by releasing the drug in the upper GI tract, provide comparablebioavailability to marketed pyridostigmine products (R1), and provideextended plasma concentration profiles for 24 hours. In certainembodiments, the gastroretentive tablets of the present disclosureprovide for reduced initial burst release, of pyridostigmine bromide ofat least 14 hours. In particular embodiments, the reduced initial burstrelease comprises an in vitro release of between about 20% and about 35%of the pyridostigmine bromide within 2 hours of dissolution in adissolution medium.

The gastroretentive pyridostigmine tablets of the disclosure providesignificant therapeutic advantages over the currently marketedpyridostigmine products with respect to the following attributes: 1)enhanced control of symptoms associated with MG with once-a-day dosing,2) rapid onset of effect/reduced lag time and consistent blood levelsduring the daytime to treat progressive muscle weakness and fatigueknown to build up by the evening, 3) reduced initial drug concentration(e.g., reduced initial burst release; minimized initial burst release)sufficient to provide therapeutic effect without GI side effects, 4)lower, but still therapeutic, blood levels during the night for treatingnighttime symptoms and providing uninterrupted sleep, 5) improvedtolerability of the drug with reduced adverse events compared tofluctuating blood levels from an IR formulation, 6) reduced treatmentburden and improved adherence/compliance due to less frequent dosing,and 7) better patient satisfaction and quality of life with improvedfunctionality throughout the day and reduced reliance on caregivers.

In certain embodiments, the gastroretentive compositions of thedisclosure can comprise an immediate release layer and an extendedrelease component. The immediate release layer comprises pyridostigminebromide, and the extended release component can comprise a core coatedwith a permeable elastic membrane. In certain embodiments, the core cancomprise pyridostigmine bromide, at least one gas-generating agent(e.g., sodium bicarbonate, calcium carbonate), at least one acid (e.g.,succinic acid), and at least one swellable water-soluble hydrophilicpolymer. In certain embodiments, the gastroretentive tablets of thedisclosure can include an orifice in the functional coat.

In certain embodiments, amounts of succinic acid and the gas-generatingagent(s) are optimized to minimize the floating lag time.

In certain embodiments, compositions of the disclosure include a sealcoat between the core and the functional coat. In certain otherembodiments, the compositions of the disclosure do not include a sealcoat between the core and the functional coat. Surprisingly, it wasobserved that absence of a seal coat between the tablet core and thefunctional coat resulted in minimizing the floating lag time. Tablets 8and 8A contained a seal coat between the tablet core and the functionalcoat; and Tablets 11/11A, 13/13A, and 15/15A did not include a seal coatbetween the tablet core and the functional coat. FIG. 10 comparesfloating lag times of Tablets 8, 11, 13, and 15, with and withoutorifice/hole, at 200 mg functional coating weight gain, and Tablets 8A,11A, 13A, and 15A, with and without orifice/hole, at 250 mg functionalcoating weight gain. The flotation studies were performed, usingRotating Bottle method at 5 rpm and 37° C., in 200 ml of a dissolutionmedium with pH 4.5 comprising 100 mM NaCl. FIG. 10 demonstrates thatTablets 8/8A, containing a seal coat, exhibit longer floating lag timescompared to tablets without a seal coat (Tablets 11/11A, 13/13A, and15/15A).

In certain embodiments, it was observed that tablets containing amixture of BENECEL® K4M PH DC (2700-5040 mPa·s) and METHOCEL® K100 PremLVCR(80-120 mPa·s) (Tablets 22, 23, and 34) provided a better controlledrelease compared to tablets containing BENECEL® K4M PH DC (Tablet 8)alone. FIGS. 17 and 23 compare in vitro dissolution profiles of Tablets8, 22, and 23; and Tablets 8 and 34, respectively. FIGS. 17 and 23demonstrate that Tablets 22, 23, and 34 (all containing a mixture ofBENECEL® K4M PH DC and METHOCEL® K100 Prem LVCR) provided bettercontrolled release compared to Tablet 8 (containing BENECEL® K4M PH DCalone).

FIGS. 20 and 21 compare pharmacokinetic data for gastroretentive Tablet34 (gastroretentive tablet with hole) and Tablet 35 (gastroretentivetablet without hole), respectively. FIGS. 20 and 21 demonstrate thatTablets 34 and 35 provide therapeutic plasma concentrations ofpyridostigmine bromide for between about 14 hours and about 20 hours.

In certain embodiments, the gastroretentive tablets of the disclosurecan include an immediate release layer and an extended releasecomponent. FIG. 23 compares in vitro dissolution profiles of a tabletcontaining an immediate release drug layer (Tablet 34), a tablet with noimmediate release drug layer (Tablet 8), and a tablet of MESTINON®TIMESPAN. The figure demonstrates that Tablet 8 (without IR drug layer)exhibits minimized initial burst release; and Tablet 34 (with IR druglayer) provides an immediate release of a therapeutic amount ofpyridostigmine bromide, with reduced initial burst release (betweenabout 20% and about 35% drug release in about 2 hours) of the drug,compared to MESTINON® TIMESPAN.

FIG. 24 compares pharmacokinetic data for gastroretentive Tablet 34, atablet with a hole in the functional coat, under LF-LC breakfastconditions (Condition I) and HF-HC breakfast conditions (Condition II),and MESTINON® TIMESPAN (Condition II). FIG. 24 demonstrates thatMESTINON® TIMESPAN provides higher drug plasma concentrations betweenabout 0 and 5 hours compared to Tablet 34 under Conditions I and II.FIG. 24 further demonstrates that Tablet 34, under Conditions I and II,provides higher drug plasma concentrations of pyridostigmine bromideover an extended time period, e.g., about 7 hours or beyond, compared toMESTINON® TIMESPAN.

In certain embodiments, the compositions of the disclosure can comprisehorizontally compressed oval, modified oval, or capsule shapes for easyswallowing. In certain embodiments, the tablets can be compressed usingoval, modified oval, capsule shaped, or any other shaping tool. Incertain embodiments, the horizontally compressed tablets can comprise along axis having a length of between about 12 mm and about 22 mm, and ashort axis having a length of between about 8 mm and about 11 mm. Incertain embodiments, the tablets can have a long axis of about 12 mm,about 13 mm, about 14 mm, about 15 mm, about 16 mm, about 17 mm, about18 mm, about 19 mm, about 20 mm, about 21 mm, about 22 mm, or anyintermediate lengths therein. In certain embodiments, the tablets canhave a short axis of about 8 mm, about 9 mm, about 10 mm, about 11 mm,or any intermediate lengths therein. In certain embodiments, thecompressed multilayered tablets can comprise a long axis having a lengthof about 20±2 mm, and a short axis having a length of between about 10±2mm. In certain embodiments, the initial tablet size (10 mm×19 mm) can bereasonably small for swallowability, and once swallowed, the tablet isdesigned for rapid generation of carbon dioxide (CO₂) within the core toincrease its buoyancy. Within 30 minutes of coming into contact withsimulated gastric medium, the tablet starts floating and transforms intoan oblong shape with major and minor axes having lengths of about 26 and18 mm respectively, which can be maintained for at least about 14 hours.

The gastroretentive tablets of the disclosure can comprise an expandinghydrophilic core and a rate-controlling membrane surrounding the core.The membrane can expand rapidly and provide a protective shell thatstretches upon hydration to accommodate the rapidly expandinghydrophilic core, and then acts as a rate-controlling membrane thatcontrols the release rate of the drug. In certain embodiments, thegastroretentive tablets of the disclosure, when in contact withsimulated gastric medium, can expand in about 60 minutes or less, to asize that prevents its passage through a pyloric sphincter. In certainembodiments, the gastroretentive tablets of the disclosure can float inabout 40 minutes or less, expand in about 60 minutes or less to a sizethat prevents its passage through pyloric sphincter, and provideextended release of pyridostigmine for about 24 hours. In certainembodiments, the gastroretentive tablets of the disclosure can float inabout 40 minutes or less in 50 mM pH 4.5 buffer containing 100 mM NaCl.In certain embodiments, the gastroretentive tablets of the disclosurecan float in about 35 minutes, about 34 minutes, about 33 minutes, about32 minutes, about 31 minutes, about 30 minutes, about 29 minutes, about28 minutes, about 27 minutes, about 26 minutes, about 25 minutes, about24 minutes, about 23 minutes, about 22 minutes, about 21 minutes, about20 minutes, about 19 minutes, about 18 minutes, about 17 minutes, about16 minutes, about 15 minutes or less, or any intermediate time periods,in 50 mM pH 4.5 buffer containing 100 mM NaCl. FIG. 10 providesflotation lag times of the compositions of the disclosure containing 200mg and 250 mg coating weight gains of the functional coat. In certainembodiments, the gastroretentive tablets of the disclosure can expand inless than about 60 minutes to a size that prevents their passage throughthe pyloric sphincter. In certain embodiments, the gastroretentivetablets of the disclosure can exhibit at least about 200% to about 800%volume gain from its original volume at 60 minutes, measured using aRotating Bottle method at about 5 rpm and about 37° C., in 200 ml of pH4.5 dissolution medium, containing about 100 mM NaCl. In certainembodiments, the gastroretentive tablets can exhibit about 200%, about250%, about 300%, about 350%, about 400%, about 450%, about 500%, about550%, about 600%, about 650%, about 700%, about 750%, about 800%, or anyintermediate values therein, volume gain from its original volume at 60minutes FIGS. 11-13 show volume expansions of the gastroretentivetablets of the disclosure, in pH 4.5 buffer containing about 100 mMNaCl. In certain embodiments, rapid expansion of the gastroretentivetablet can result from an initial expansion of the permeable elasticmembrane and a simultaneous swelling of the hydrophilic core to supportthe expanded membrane.

In certain embodiments, the hydrophilic core can swell to a size thatcan support the expanded permeable elastic membrane. In certainembodiments, the permeable elastic membrane can keep the core intact ina swollen condition for a sufficient period of time, and provides thedesired characteristics of drug release.

In certain embodiments, the gastroretentive tablets of the disclosuremarkedly improve absorption and bioavailability of pyridostigminebromide.

In certain embodiments, the gastroretentive tablets of the disclosurecan provide gastric retention of pyridostigmine bromide for up to about24 hours. In certain embodiments, the gastroretentive tablets of thedisclosure can provide gastric retention of pyridostigmine bromide forbetween, e.g., about 10 to about 24 hours, about 12 to about 24 hours,and about 14 to about 24 hours. In certain embodiments, thegastroretentive tablets of the disclosure can provide gastric retentionof pyridostigmine bromide for at least about 14 hours. In certainembodiments, the gastroretentive tablets of the disclosure can maintainits integrity in a swollen state for a period of at least about 14hours. In certain embodiments, the gastroretentive tablets of thedisclosure can provide gastric retention of pyridostigmine bromide forabout 24 hours. Furthermore, as the drug diffuses out of the core andthe polymeric excipients in the core continue to swell, the plasticizercan leach out and the permeable elastic membrane can lose its integrityand starts to break, thereby allowing remnants of the drug formulationand the remaining contents to be expelled from the stomach at anappropriate time, e.g., after a prolonged period of drug release. FIG.19 provides schematic and photographic representations of thegastroretentive tablets of the disclosure from its initial tablet formto its residue after complete drug release.

6.2.3. Pellets

In certain embodiments, compositions of the disclosure can be formulatedas granules or pellets. In certain embodiments, the compositions of thedisclosure can be formulated as pyridostigmine bromide pellets. Incertain embodiments, the pellets can comprise a pyridostigmine bromidecontaining core coated with a functional coat/membrane. In certainembodiments, the pyridostigmine bromide containing core can be furtherdrug-layered with a pyridostigmine bromide layer.

In certain embodiments, there can be a seal coat between thepyridostigmine bromide containing core and the functional coat/membrane,and/or between the pyridostigmine bromide layer and the functionalcoat/membrane. In certain embodiments, the functional coat can befurther coated with an immediate release drug layer comprisingpyridostigmine bromide. In certain embodiments, the immediate releasedrug layer is further coated with an overcoat. In certain embodiments,there is a seal coat between the immediate release drug layer and thefunctional coat, and/or between the immediate release drug layer and theovercoat.

In certain embodiments, the pellets can comprise a microcrystallinecellulose core (MCC), also known as a cellet. In certain embodiments,the MCC core or cellet is drug-layered with a pyridostigmine bromidelayer. In certain embodiments, the drug layer can be further coated witha functional coat. In certain embodiments, there can be a seal coatbetween the drug layer and the functional coat.

In certain embodiments, the drug layer over the pyridostigminecontaining core or the cellet core can comprise pyridostigmine bromide,a water-insoluble polymer, a plasticizer, and/or an anti-tacking agent.

In certain embodiments, the water-insoluble polymer can beethylcellulose.

In certain embodiments, the anti-tacking agent can be one or more ofsilicon dioxide (SYLOID® 244FP), fumed silica (CAB-O-SIL®), talc,kaolin, or combinations thereof. In certain embodiments, the plasticizercomprises triethyl citrate, triacetin, polyethylene glycol, propyleneglycol, dibutyl sebacate, or combinations thereof. In certainembodiments, the plasticizer can be triethyl citrate. In certainembodiments, the plasticizer can be dibutyl sebacate.

In certain embodiments, the drug layer can comprise pyridostigminebromide, ethylcellulose, dibutyl sebacate, and talc. In certainembodiments, the drug layer can comprise pyridostigmine bromide,hypromellose, and talc.

In certain embodiments, the seal coat can comprise at least onewater-soluble polymer comprising hypromellose and/or hydroxypropylcellulose.

In certain embodiments, the functional coat can comprise at least onewater-insoluble lipophilic material and, optionally, at least onewater-soluble hydrophilic polymer. In certain embodiments, thefunctional coat can comprise at least one water-insoluble lipophilicpolymer and at least one water-soluble hydrophilic polymer (i.e., a poreformer).

In certain embodiments, the water-insoluble lipophilic material in thefunctional coat/membrane can be selected from the group comprising, butnot limited to, ethyl acrylate and methyl methacrylate copolymer(EUDRAGIT® NE, EUDRAGIT® NM), ammonio methacrylate copolymer (EUDRAGIT®RL PO, EUDRAGIT® RS PO), carnauba wax, stearic acid, ethylcellulose(ETHOCEL™), cellulose acetate, and polyvinyl acetate dispersion(KOLLICOAT® SR). In certain embodiments, the water-soluble hydrophilicpolymer comprises, but is not limited to, polyethylene glycol (PEG 400,PEG 1000, PEG 1450, PEG 3350), hydroxypropyl cellulose, polyvinylpyrolidone (PVP), KOLLIDON® 30, KOLLICOAT® IR, mannitol, andmethylcellulose (METHOCEL™ E3, METHOCEL™ E5, METHOCEL™ E6).

In certain embodiments, the functional coat further can comprise atleast one plasticizer and at least one anti-tacking agent. Usefulanti-tacking agents can include, but are not limited to, silicon dioxide(SYLOID® 244FP), fumed silica (CAB-O-SIL®), talc, kaolin, andcombinations thereof. Useful plasticizers include, but are not limitedto, triethyl citrate, triacetin, polyethylene glycol, propylene glycol,and dibutyl sebacate. In certain embodiments, the plasticizer can betriethyl citrate. In certain embodiments, the plasticizer can be dibutylsebacate.

In certain embodiments, the pellets can be retained in capsules. Incertain embodiments, a composition can consist of pellets consolidatedinto a packed mass for ingestion, even though the packed mass willseparate into individual pellets after ingestion. Conventional methodscan be used for consolidating the pellets in this manner. For example,the pellets can be placed in gelatin capsules known in the art as“hard-filled” capsules and “soft-elastic” capsules. The compositions ofthese capsules and procedures for filling them are known among thoseskilled in drug formulations and manufacture. The encapsulating materialshould be highly soluble so that the particles are freed and rapidlydispersed in the stomach after the capsule is ingested. In certainembodiments, the pellets can be incorporated directly into food assprinkles.

In certain embodiments, the present disclosure provides for apyridostigmine bromide pellet comprising an inert core, a drug layercontaining pyridostigmine bromide over the inert core, and a membraneover the drug layer, wherein the membrane comprises a water-insolublelipophilic polymer and a water-soluble hydrophilic polymer, and whereinthe pellet provides extended release, with minimized initial burstrelease, of pyridostigmine bromide, for at least about 14 hours. Incertain embodiments, the water-insoluble lipophilic polymer of thepellet of the present disclosure is selected from the group consistingof an ethyl acrylate and methyl methacrylate copolymer, an ammoniomethacrylate copolymer, ethylcellulose, cellulose acetate, polyvinylacetate, and mixtures thereof. In certain embodiments, the water-solublehydrophilic polymer of the pellet of the present disclosure is selectedfrom the group consisting of polyethylene glycol, hydroxypropylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polyvinylpyrolidone, methylcellulose, xanthan gum, guar gum, sodium alginate,starch, a copolymer of polyvinyl acetate and polyvinyl pyrolidone, acopolymer of ethylene glycol and propylene glycol, a copolymer ofpolyvinyl alcohol and polyethylene glycol, and mixtures thereof. Incertain embodiments, the pellet of the present disclosure furthercomprises a seal coat between the drug layer and the membrane. Incertain embodiments, the seal coat of the pellet of the presentdisclosure comprises a water-soluble polymer selected from the groupconsisting of a polyvinyl alcohol-based polymer, methyl cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, and mixtures thereof. In certain embodiments, thewater-soluble polymer of the pellet of the present disclosure ishypromellose, hydroxypropyl cellulose, or a mixture thereof.

In certain embodiments, the pellets can comprise from about 100 mg toabout 250 mg, from about 150 mg to about 200 mg, or about 180 mg ofpyridostigmine bromide in a pyridostigmine bromide containing core. Incertain embodiments, the pellets can comprise a seal coat. In certainembodiments, the seal coat can comprise from about 5 mg to about 30 mg,from about 10 mg to about 20 mg, or about 15 mg of hydroxypropylcellulose. In certain embodiments, the seal coat can further comprisefrom about 1 mg to about 10 mg, from about 2 mg to about 5 mg, or about3 mg of talc. In certain embodiments, the pellets can further comprise afunctional coat. The functional coat can comprise from about 10 mg toabout 50 mg, from about 20 mg to about 40 mg, or from about 25 mg toabout 35 mg of ethyl cellulose. In certain embodiments, the functionalcoat can further comprise from about 1 mg to about 10 mg, from about 2mg to about 5 mg, or about 3 mg of triethyl citrate. In certainembodiments, the functional coat can further comprise from about 1 mg toabout 10 mg, from about 2 mg to about 5 mg, or about 3 mg of talc. Incertain embodiments, the functional coat can further comprise from about1 mg to about 10 mg, from about 2 mg to about 5 mg, or about 3 mg ofhydroxypropyl methylcellulose with a viscosity of between about 4 cp and6 cp.

In certain embodiments, the present disclosure provides for apyridostigmine bromide pellet comprising an inert core, a drug layercontaining pyridostigmine bromide over the inert core, and a membraneover the drug layer, wherein the membrane comprises a water-insolublelipophilic polymer and a water-soluble hydrophilic polymer, and whereinthe pellet provides extended release, with minimized initial burstrelease, of pyridostigmine bromide, for at least about 14 hours. Incertain embodiments, the water-insoluble lipophilic polymer of thepellet of the present disclosure is selected from the group consistingof an ethyl acrylate and methyl methacrylate copolymer, an ammoniomethacrylate copolymer, ethylcellulose, cellulose acetate, polyvinylacetate, and mixtures thereof. In certain embodiments, the water-solublehydrophilic polymer of the pellet of the present disclosure is selectedfrom the group consisting of polyethylene glycol, hydroxypropylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polyvinylpyrolidone, methylcellulose, xanthan gum, guar gum, sodium alginate,starch, a copolymer of polyvinyl acetate and polyvinyl pyrolidone, acopolymer of ethylene glycol and propylene glycol, a copolymer ofpolyvinyl alcohol and polyethylene glycol, and mixtures thereof. Incertain embodiments, the pellet of the present disclosure furthercomprises a seal coat between the drug layer and the membrane. Incertain embodiments, the seal coat of the pellet of the presentdisclosure comprises a water-soluble polymer selected from the groupconsisting of a polyvinyl alcohol-based polymer, methyl cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, and mixtures thereof. In certain embodiments, thewater-soluble polymer of the pellet of the present disclosure ishypromellose, hydroxypropyl cellulose, or a mixture thereof.

In certain embodiments, the pellets can comprise from about 20 mg toabout 150 mg, from about 50 mg to about 100 mg, or from about 70 mg toabout 80 mg of pyridostigmine bromide granules in a pyridostigminebromide containing core. In certain embodiments, the pellet can furthercomprise a drug layer. In certain embodiments, the drug layer cancomprise from about 50 mg to about 200 mg, from about 75 mg to about 150mg, or from about 95 mg to about 105 mg of pyridostigmine bromide. Incertain embodiments, the drug layer can further comprise from about 10mg to about 40 mg, from about 15 mg to about 30 mg, or from about 20 mgto about 25 mg of hydroxypropyl methylcellulose. In certain embodiments,the drug layer can further comprise from about 1 mg to about 10 mg, fromabout 2 mg to about 8 mg, or from about 3 mg to about 5 mg of talc. Incertain embodiments, the pellets can further comprise a seal coat. Incertain embodiments, the seal coat can comprise from about 5 mg to about30 mg, from about 10 mg to about 25 mg, or from about 15 mg to about 20mg of hydroxypropyl cellulose. In certain embodiments, the seal coat canfurther comprise from about 1 mg to about 10 mg, from about 2 mg toabout 8 mg, or from about 3 mg to about 5 mg of talc. In certainembodiments, the pellets can further comprise a functional coat. Incertain embodiments, the functional coat can comprise from about 10 mgto about 100 mg, from about 25 mg to about 80 mg, or from about 50 mg toabout 75 mg of ethyl cellulose. In certain embodiments, the functionalcoat can further comprise from about 2 mg to about 15 mg, from about 2mg to about 10 mg, or from about 5 mg to about 8 mg of triethyl citrate.In certain embodiments, the functional coat can further comprise fromabout 2 mg to about 15 mg, from about 2 mg to about 10 mg, or from about5 mg to about 8 mg of talc.

In certain embodiments, the pellets can comprise a cellet core. Incertain embodiments, the pellet comprises about 100 mg of cellet core.In certain embodiments, the pellets can further comprise a drug layer.In certain embodiments, the drug layer can comprise from about 100 mg toabout 300 mg, from about 125 mg to about 250 mg, or from about 150 mg toabout 200 mg of pyridostigmine bromide. In certain embodiments, the druglayer can further comprise from about 10 mg to about 60 mg, from about20 mg to about 50 mg, or from about 30 to about 40 mg of ethylcellulose. In certain embodiments, the drug layer can further comprisefrom about 1 mg to about 10 mg, from about 2 mg to about 7 mg, or fromabout 3 mg to about 5 mg of dibutyl sebacate. In certain embodiments,the drug layer can further comprise from about 1 mg to about 15 mg, fromabout 5 mg to about 10 mg, or about 6 mg of talc. In certainembodiments, the pellet can further comprise a seal coat. In certainembodiments, the seal coat can comprise from about 10 mg to about 100mg, from about 10 mg to about 85 mg, from about 50 mg to about 75 mg, orfrom about 15 mg to about 20 mg of hydroxypropyl methylcellulose. Incertain embodiments, the seal coat can further comprise from about 1 mgto about 10 mg, from about 2 mg to about 8 mg, or from about 3 mg toabout 5 mg of talc. In certain embodiments, the pellet can furthercomprise a functional coat. In certain embodiments, the functional coatcan comprise from about 20 mg to about 120 mg, from about 30 mg to about100 mg, from about 45 to about 85 mg, or from about 50 mg to about 75 mgof ethylcellulose. In certain embodiments, the functional coat canfurther comprise from about 5 mg to about 30 mg, from about 10 mg toabout 25 mg, or from about 12 mg to about 18 mg of dibutyl sebacate. Incertain embodiments, the functional coat can further comprise from about1 mg to about 20 mg, from about 5 mg to about 15 mg, or from about 7 mgto about 13 mg of talc. In certain embodiments, the functional coat canfurther comprise from about 0.5 mg to about 5 mg, from about 1 mg toabout 4 mg, or from about 2 mg to about 3 mg of fumed silica. In certainembodiments, the functional coat can further optionally comprise fromabout 0.5 mg to about 15 mg, from about 1 mg to about 10 mg, or fromabout 1.5 mg to about 2.5 mg of hydroxypropyl methylcellulose. Incertain embodiments, the functional coat can further optionally comprisefrom about 20 mg to about 150 mg, from about 50 mg to about 120 mg, orfrom about 75 mg to about 100 mg of cellulose acetate. In certainembodiments, the functional coat can further optionally comprise fromabout 5 mg to about 40 mg, from about 10 mg to about 25 mg, or fromabout 15 mg to about 20 mg of polyethylene glycol.

6.3. Methods of Making

In certain embodiments, the present disclosure provides extended releasepyridostigmine compositions suitable for maintaining stable plasmaconcentrations, with minimized initial burst release/dose dumping, ofpyridostigmine bromide. In certain embodiments, the compositions of thedisclosure can provide extended release of pyridostigmine bromide for atleast about 14 hours. The extended release pyridostigmine compositionsof the disclosure can include matrix tablets, and pellets suitable fordosing in capsules, sachets, and as sprinkles on food. In certainembodiments, the pyridostigmine compositions can comprisegastroretentive tablet compositions providing extended release ofpyridostigmine for at least about 14 hours. In certain embodiments,gastroretentive pyridostigmine compositions of the disclosure aresuitable for once-daily administration.

In certain embodiments, the pyridostigmine compositions of thedisclosure can be direct compression tablets. The tablets can be made bymixing pyridostigmine bromide, a water-insoluble lipophilic polymer, afiller, a lubricant, and a glidant into a uniform blend; compressing theblend into a tablet core; and coating the tablet core with a functionalcoat/membrane. In certain embodiments, there can be a seal coat betweenthe tablet core and the functional coat. In certain embodiments, thepyridostigmine compositions of the disclosure can include pyridostigminegranules that are made by hot-melt extrusion. In certain embodiments,the hot-melt extruded pyridostigmine granules can be mixed withextragranular excipients into a uniform blend, and the uniform blend canbe compressed into a tablet. In certain embodiments, the matrix tabletscan be further coated with an IR drug layer comprising pyridostigminebromide and a binder, using a perforated pan coater.

In certain embodiments, the pyridostigmine compositions of thedisclosure can be gastroretentive tablets. The tablets can be made bymixing pyridostigmine bromide, one or more gas-generating agents, anacid, a wicking agent, a filler, and a glidant into a uniform blend;adding lubricant to the resulting blend and compressing the blend into atablet core; coating the tablet core with a seal coat comprising aqueousdispersion of hydroxypropyl cellulose; coating the seal-coated tabletswith a functional coat comprising a plasticizer, and at least one ofethyl acrylate and methyl methacrylate copolymer (EUDRAGIT® NE,EUDRAGIT® NM), and an ammonio methacrylate copolymer (EUDRAGIT® RL PO,EUDRAGIT® RS PO). In certain embodiments, the functional coat cancomprise a plasticizer, and an ammonio methacrylate copolymer (EUDRAGIT®RL PO, EUDRAGIT® RS PO). In certain embodiments, the gastroretentivetablets can be further coated with an IR drug layer comprisingpyridostigmine bromide and a binder, using a perforated pan coater.

In certain embodiments, the pyridostigmine compositions of thedisclosure can comprise pyridostigmine pellets suitable for dosing incapsules, sachets, and as sprinkles on food. In certain embodiments, thepellets can comprise a pyridostigmine bromide core. In certainembodiments, the pellets can comprise a cellet. In certain embodiments,the pellet cores (e.g., pyridostigmine bromide cores or cellets) arefurther drug-layered with pyridostigmine bromide. In certainembodiments, the pellets are made by coating the pyridostigmine bromidecore with a seal coat comprising a water-soluble hydrophilic polymer;coating the seal-coated pellets with a functional coat comprising aplasticizer, a water-insoluble lipophilic polymer that is insoluble inphysiological fluids, and a pore former comprising a water-solublehydrophilic polymer. In certain embodiments, the pyridostigmine bromidecores are further drug-layered with pyridostigmine bromide.

In certain embodiments, various solvents used in processes of thedisclosure include, but are not limited to, water, methanol, ethanol,acetone, isopropyl alcohol, and mixtures thereof. In certainembodiments, the solvent is a mixture of acetone and water, a mixture ofethanol and isopropyl alcohol, a mixture of acetone and isopropylalcohol, a mixture of isopropyl alcohol and water, or a mixture ofwater, ethanol, and isopropyl alcohol. In certain embodiments, thesolvent is a mixture of acetone and water. In certain embodiments, theratio of solvent and water ranges from about 70:30 to about 99:1. Incertain embodiments, the ratio of acetone and water is about 70:30,about 75:25, about 80:20, about 85:15, about 90:10, about 95:5, orintermediate ranges therein.

6.4. Methods of Treatment

In certain embodiments, the disclosure provides a method for treatingmyasthenia gravis (MG), postoperative bowel bloating, and urinaryretention in a patient. In certain embodiments, the disclosure providesa method for treating or preventing organophosphorus or nerve gaspoisoning or injuries. In certain embodiments, the disclosure provides amethod for treating dementia, including Alzheimer's disease. The methodscomprise administering to a patient or a person in need thereof, anextended release pyridostigmine bromide dosage form of the disclosure.The dosage form is suitable for once- or twice-daily administration. Incertain embodiments, the dosage forms of the present disclosure areadministered QD as a single dosage unit. In certain embodiments, thecompositions of the disclosure are administered QD as multiple dosageunits (e.g., two, three, or four dosage units). In certain embodiments,the dose strength and dosing frequency is determined based on thecondition being treated and the severity of the condition.

In certain embodiments, the disclosure provides a method for improvingpatient compliance by administering extended release pyridostigminebromide dosage forms of the disclosure, wherein the compositions providean extended release, with no initial dose dumping compared to marketedextended release pyridostigmine products. In certain embodiments, theextended release pyridostigmine dosage forms of the disclosure improvepatient compliance by including an IR drug layer that provides a drugplasma concentration sufficient to overcome the lag time inpyridostigmine release seen without application of an IR layer, andsufficient to provide instant therapeutic effects, with reduced oreliminated GI side effects; the extended release component providescontrolled extended release of the drug for a period of at least about14 hours.

In certain embodiments, the disclosure provides a method for improvingpatient compliance by administering an extended release pyridostigminebromide dosage forms of the disclosure, wherein the extended releasedosage forms will allow for reduced frequency of administration of thecomposition. In certain embodiments, the dosage forms of the disclosurereduce initial burst release/minimize initial burst release whileproviding a therapeutically effective amount of pyridostigmine bromidefor periods of about 12 hours to about 24 hours.

In certain embodiments, the disclosure provides methods for improvingpatient compliance by administering, to a patient or a subject in needthereof, an extended release pyridostigmine bromide dosage forms of thedisclosure, reducing or minimizing initial burst release ofpyridostigmine bromide, and providing the desired therapeutic effectwith minimal side effects including nausea, vomiting, diarrhea,abdominal cramps, fasciculations, increased peristalsis, increasedsalivation, increased bronchial secretions, miosis, and diaphoresis. Themethods comprise administering to the patient an extended releasepyridostigmine bromide dosage form of the disclosure. The extendedrelease dosage forms of the disclosure are suitable for once- ortwice-daily administration.

In certain embodiments, the present disclosure provides for atherapeutic method for treating myasthenia gravis, comprising orallyadministering to a subject in need thereof a single QD gastroretentivepyridostigmine bromide tablet, wherein the tablet provides an extendedrelease, with minimized initial burst release, of pyridostigmine bromidefor up to about 24 hours, and wherein the minimized initial burstrelease comprises release of not more than 20% of pyridostigmine bromidewithin two hours of dissolution in a dissolution medium. In certainembodiments, the dissolution medium comprises 50 mM of pH 4.5 acetatebuffer with 100 mM NaCl. In certain embodiments, the present disclosureprovides for a method for reducing GI side effects in a patientconsuming a pyridostigmine composition, the method comprisingadministering to the patient a gastroretentive pyridostigminecomposition comprising an immediate release layer and an extendedrelease component as a single tablet/day, wherein the compositionprovides an extended release, with a reduced initial burst release, ofpyridostigmine bromide for at least about 14 hours, and wherein thereduced initial burst release comprises release of between 20% and 35%of pyridostigmine bromide within two hours of dissolution of thecomposition into a dissolution medium.

In certain embodiments, the present disclosure provides for a method forimproving patient compliance in a patient consuming a pyridostigminecomposition, the method comprising administering to the patient agastroretentive pyridostigmine composition comprising an immediaterelease layer and an extended release component as a single tablet/day,wherein the composition provides an extended release, with a reducedinitial burst release, of pyridostigmine bromide for at least about 14hours.

7. EXAMPLES

The following examples illustrate the disclosure in a nonlimitingmanner. Unless indicated to the contrary, the numerical parameters setforth herein can vary depending upon the desired properties sought to beobtained by the present disclosure.

Example 1 Pyridostigmine Bromide Matrix Tablet Compositions (180 mg)

The present example provides various formulations for pyridostigminebromide tablets as outlined in Table 1 and Table 2. Seven differenttablets were prepared.

TABLE 1 Formulation of Matrix Tablets Tablet 1 Tablet 2 Tablet 3 Tablet4 Tablet 5 Ingredients (mg) (mg) (mg) (mg) (mg) Pyridostigmine 180.0180.0 180.0 180.0 180.0 bromide Stearic acid — 180.0 — 20.00 20.00Carnauba wax — — — 160.00 80.00 Ethylcellulose — — — — — (ETHOCEL ™)Silicon dioxide 180.0 — 180.0 — 80.00 (SYLOID ® 244FP) Fumed silica —20.00 20.00 20.00 20.00 (CAB-O-SIL ®) Mannitol 100.0 100.0 100.0 100.0100.0 (PARTECK ® M200 Magnesium 5.00 5.00 5.00 5.00 5.00 stearate CoreTablet 465.0 485.0 485.0 485.0 485.0 Weight Functional Coat Cellulose40.40 41.73 41.73 41.73 41.73 acetate Polyethylene 2.02 2.08 2.08 2.082.08 glycol (PEG 3350) Methylcellulose 4.004 4.173 4.173 4.173 4.173(METHOCEL ™ E5) Solvent* acetone:water (95:5) q.s. Total Tablet 511.42532.98 532.98 532.98 532.98 Weight *Removed during process

TABLE 2 Formulation of Matrix Tablets Ingredients Tablet 6** (mg) Tablet7 (mg) Pyridostigmine bromide 150.00 180.00 Stearic acid — 90.00Ethylcellulose 100.00 — (ETHOCEL ™) Silicon dioxide 20.00 — (SYLOID ®244FP) Fumed silica — 10.00 (CAB-O-SIL ®) Mannitol 100.00 100.00(PARTECK ®M200) Magnesium stearate 5.00 5.00 Core Tablet Weight 375.00385.00 Functional Coat Cellulose acetate 62.50 33.40 Polyethylene glycol6.25 1.67 (PEG 3350) Methylcellulose 6.25 3.34 (METHOCEL ™ E5) Solvent*acetone:water (95:5) q.s. Total Weight 450.00 423.41 *Removed duringprocess **Tablet 6 can have an IR coat of 30 mg of pyridostigminebromide

Tablets 1-5 and Tablet 7 contain 180 mg of pyridostigmine bromide andinclude 10% coating weight gain of uncoated tablet. Tablets 1-5 and 6 donot contain ethylcellulose. Tablet 6 contains 150 mg of pyridostigminebromide, ethylcellulose, and 20% coating weight gain of uncoated tablet.Tablets 1-7 were made according to the following general procedure.

Manufacturing Procedure:

-   -   1. A uniform blend of pyridostigmine, stearic acid, carnauba        wax, ethylcellulose, silicon dioxide, fumed silica, mannitol,        and magnesium stearate was made as per Tablets 1-7.    -   2. For each blend, the drug and the excipients were taken in a        V-blender and mixed to obtain a uniform blend.    -   3. Magnesium stearate was sieved through sieve #30 and mixed        with the uniform blend from step #2.    -   4. Required amount of blend was filled into the die and then        compressed as tablet compositions.    -   5. Cellulose acetate and methylcellulose were added to a        stainless steel container charged with an acetone and water        mixture in a ratio of 95:5 and mixed to obtain a clear solution.    -   6. Polyethylene glycol 3350 was added to the solution from step        #4 and mixed for not less than about 30 minutes.    -   7. The tablets from step #4 were taken in a coating pan and        coated with the solution from step #6 until the target weight        gain was attained.

FIG. 2 depicts a schematic representation of pyridostigmine matrixtablets, with and without an immediate release drug layer.

Example 2 Pyridostigmine Bromide Gastroretentive Tablet Compositions

The present Example provides various formulations for pyridostigminebromide gastroretentive tablets as outlined in Table 3.

TABLE 3 Formulation of Pyridostigmine Bromide Tablets Tablet 8 Tablet 9Tablet 10 Tablet 11 Tablet 12 Ingredients (mg/dose) (mg/dose) (mg/dose)(mg/dose) (mg/dose Pyridostigmine 180.0 180.0 180.0 135.0 135.0 bromideSuccinic acid, NF- 50.0 50.0 50.0 80.0 80.0 micronized Sodiumbicarbonate 50.00 50.0 50.0 55.0 55.0 Calcium carbonate 125.0 125.0125.0 65.0 65.0 Crospovidone 100.0 100.0 100.0 200.0 100.0 PARTECK ®M200 233.0 233.0 233.0 153.0 253.0 BENECEL ™ K4M PH 200.0 300.0 200.0 —100.0 DC BENECEL ™ K200M — — 25.0 — — METHOCEL ™ K100 — — — 300.0 200.0Prem LVCR CAB-O-SIL ® 4.00 4.00 4.00 4.00 4.00 Magnesium stearate 8.008.00 8.00 8.00 8.00 Total weight 950.0 1050.0 975.0 1000.0 1000.0 SealCoat Hydroxypropyl 33.33 33.33 33.33 — — cellulose Talc 3.33 3.33 3.33 —— Triethyl citrate 3.33 3.33 3.33 — — Solvent* q.s. q.s. q.s. q.s. q.s.acetone:water (95:5) Functional Coat EUDRAGIT ® RL PO 148.15 148.15148.15 148.15 148.15 Triethyl citrate 22.22 22.22 22.22 22.22 22.22 Talc29.63 29.63 29.63 29.63 29.63 Solvent* acetone:water q.s. q.s. q.s. q.s.q.s. (95:5) Over Coat OPADRY ® white 15.00 15.00 15.00 — —Solvent*Purified water, q.s. q.s. q.s. USP Total weight 1205.00 1305.001230.00 1200.0 1200.0 *Removed during process

Tablets 8-10 contain 180 mg of pyridostigmine, 50 mg of succinic acid,50 mg of sodium bicarbonate, 125 mg of calcium carbonate, and BENECEL™K4M-DC. Tablet 10 further contains BENECEL™ 200M. Tablets 11-12 contain135 mg of pyridostigmine bromide, and 80 mg of succinic acid, 55 mg ofsodium bicarbonate, and 65 mg of calcium carbonate. Further, Tablet 11contains METHOCEL™ K100 Premium LVCR and Tablet 12 contains a mixture ofMETHOCEL™ K100 Premium LVCR and BENECEL™ K4M PH DC. Tablets 8-12 weremade according to the following general procedure.

Manufacturing Procedure:

A. Core Tablets

-   1. Pyridostigmine, succinic acid, sodium bicarbonate, calcium    carbonate, crospovidone, PARTECK® M200, BENECEL™ K4M-DC, BENECEL™    K200M, METHOCEL™ K100 Premium LVCR, and CAB-O-SIL®, as per Tablets    8-12, were sieved through sieve #20 and mixed to obtain a uniform    blend.-   2. Magnesium stearate was sieved through sieve #30 and mixed with    the uniform blend from step #1.-   3. The resulting blend from step #2 was compressed to obtain    pyridostigmine tablet cores.    B. Seal Coating-   1. Hydroxypropyl cellulose, triethyl citrate, and talc were added to    a mixture of acetone and water (95:5) in a stainless steel container    and mixed to form a uniform dispersion.-   2. Tablet cores 8-10 were seal coated using a perforated pan coater    with an inlet air temperature of 25° C.-60° C. at a product    temperature of 25-45° C.-   3. The coated tablet cores were dried in the coating pan.    C. Functional Coating and Over Coat-   1. EUDRAGIT® RL PO was added to acetone and water mixture (95:5) and    mixed to obtain a clear solution.-   2. To the solution from step #1, triethyl citrate was added and    mixed for at least 45 minutes.-   3. To the solution from step #2, talc was added and mixed for at    least 60 minutes to obtain a homogeneous dispersion.-   4. The homogeneous dispersion from step #3 was sprayed onto the seal    coated tablet cores 8-10 and tablet cores without seal coat, e.g.,    Tablet cores 11-12.-   5. The coated tablets from step #4 were dried in a coating pan.-   6. An orifice was laser drilled in the coated tablets from step #5    such that the orifice passed through various coating layers.-   7. Weighed quantity of opadry white was added into the required    amount of purified water. The suspension was mixed until a uniform    dispersion was formed.-   8. The functional coated tablets from step #6 were further coated    with the dispersion from step #7 in a perforated coating pan with    inlet air temperature at 25°-45° C.-   9. The coated tablets from step #8 were dried in a pan to a moisture    content below 3.0%, as measured by loss on drying at 105° C.

FIG. 4 provides a comparison of dissolution profiles of pyridostigminebromide gastroretentive Tablets 8, 9 and 10, using USP I-custombasket-dissolution apparatus, in pH 4.5 acetate buffer, at 100 RPM. FIG.4 demonstrates that Tablets 8-10 provide extended release, withminimized initial burst release, of pyridostigmine bromide for a periodof about 22 hours.

Example 3 Pyridostigmine Bromide Pellet Composition ComprisingPyridostigmine Bromide Granule Core

The present Example provides for a pyridostigmine bromide pelletcomposition comprising a pyridostigmine bromide core as outlined inTable 4.

TABLE 4 Formulation of Pyridostigmine Bromide Pellet Pellet 1Ingredients mg/dose Pyridostigmine bromide granules 180.00 Seal CoatHydroxypropyl cellulose (KLUCEL ™) 15.00 Talc 3.00 Functional coat Ethylcellulose (ETHOCEL ™ 20 cp) 30.40 Triethyl citrate 3.00 Talc 3.00METHOCEL ™ E5 Premium LV 3.00 Solvent* ethanol:water (90:10) q.s. TotalWeight 237.40 *Removed during process

Pellet 1 contains pyridostigmine bromide granule as pellet core, and afunctional coat comprising ETHOCEL™ 20 cp, METHOCEL™ E5 Premium LV, andtriethyl citrate. Pellet 1 was made according to the following generalprocedure.

Manufacturing Procedure:

A. Seal Coating

-   1. Hydroxypropyl cellulose was added to dehydrated alcohol in a    stainless steel container and mixed to form a uniform solution.-   2. To the dispersion from step #1, the purified water was added and    mixed until a clear solution formed.-   3. To the solution from step #2, talc was added and mixed for not    less than about 30 minutes to form a homogenous dispersion.-   4. Pyridostigmine bromide granules were coated using a Wurster fluid    bed coater with an inlet air temperature of 30-50° C., and    sufficient air volume for fluidization. When the product temperature    reached 30° C., the dispersion from step #3 was sprayed onto the    granules while maintaining the product temperature of 25-35° C. and    sufficient air volume for the fluidization, until the target coating    weight gain was achieved.    B. Functional Coating-   1. Ethyl cellulose and METHOCEL™ E5 Premium LV were added to    dehydrated alcohol in a stainless steel container and mixed for    about 1 hour to form a uniform dispersion.-   2. To the dispersion from step #1, water was added and mixed to    obtain a homogeneous dispersion.-   3. To the dispersion from step #2, TEC was added and mixed for not    less than about 15 minutes.-   4. To the dispersion from step #3, talc was added and mixed for not    less than about 30 minutes to obtain a uniform dispersion.-   5. Seal coated pyridostigmine bromide granules (procedure A, above)    were taken in a Wurster chamber and coated with the dispersion from    step #4, until target coating weight gain was achieved.

Example 4 Pyridostigmine Bromide Pellet Composition ComprisingPyridostigmine Bromide Granule Core and Drug Layer containingPyridostigmine Bromide

The present Example provides for a pyridostigmine bromide pelletcomposition comprising a pyridostigmine bromide granule core and a druglayer containing pyridostigmine bromide. Two different pellets wereprepared as outlined in Table 5.

TABLE 5 Formulation of Pyridostigmine Bromide Pellet Pellet 2 Pellet 3Ingredients mg/dose mg/dose Pyridostigmine 78.16 78.16 bromide granulesDrug Layer Pyridostigmine bromide 101.84 101.84 METHOCEL ™ E5 Premium LV20.36 20.36 Talc 4.07 4.07 Solvent* ethanol:water (85:15) q.s. Seal CoatHydroxypropyl cellulose 17.04 17.04 (KLUCEL ™ LF) Talc 3.40 3.40Solvent* acetone:water(95:5) q.s. Functional Coat Ethyl cellulose 56.20— (ETHOCEL ™ 20 cp) Ethyl cellulose — 74.90 (ETHOCEL ™ 45 cp) Triethylcitrate 5.60 7.50 Talc 5.60 7.50 Solvent* ethanol:water (90:10) q.s.Total Weight 292.27 314.77 *Removed during process

Pellets 2 and 3 contain pyridostigmine bromide granules as pellet coreand a pyridostigmine bromide drug layer over the pellet core. Pellet 2contains 30 wt % functional coat, of the seal coated pellet core, andPellet 3 contains 40 wt % functional coat, of the seal coated pelletcore. Pellets 2 and 3 were made according to the following generalprocedure.

Manufacturing Procedure:

A. Drug Layering

-   1. Pyridostigmine bromide and METHOCEL™ E5 Premium LV were added to    a mixture of ethanol and water (85:15) and mixed for not less than    about 60 minutes to obtain a solution.-   2. To the solution from step #1, talc was added and mixed for not    less than about 30 minutes to obtain a uniform dispersion.-   3. Pyridostigmine bromide granules were coated using a Wurster fluid    bed coater, with an inlet air temperature of about 30-50° C., and    sufficient air volume for fluidization.-   4. When the product temperature reached 30° C., the dispersion from    step #3 was sprayed onto the pyridostigmine bromide granules while    maintaining the product temperature of 25-35° C. and sufficient air    volume for the fluidization, until the target coating weight gain    was achieved.    B. Seal Coating-   1. Hydroxypropyl cellulose was added to acetone in a stainless steel    container and mixed to form a uniform solution.-   2. To the solution from step #1, the purified water was added and    mixed until a clear solution was obtained.-   3. To the solution from step #2, talc was added and mixed for not    less than about 30 minutes to form a homogenous dispersion.-   4. Pyridostigmine granules were coated using a Wurster fluid bed    coater with an inlet air temperature of 30-50° C., and sufficient    air volume for fluidization. When the product temperature reached    30° C., the dispersion from step #3 was sprayed onto the granules    while maintaining the product temperature of 28-30° C. and    sufficient air volume for the fluidization, until the target coating    weight gain was achieved.    C. Functional Coating-   1. ETHOCEL™ 20 cp/ETHOCEL™ 45 cp were added to dehydrated alcohol in    a stainless steel container and mixed for not less than about 60    minutes to obtain a uniform dispersion.-   2. To the dispersion from step #1, water was added and mixed for not    less than about 30 minutes to obtain a homogeneous dispersion.-   3. To the dispersion from step #2, TEC was added and mixed for not    less than about 45 minutes.-   4. To the dispersion from step #3, talc was added and mixed for not    less than about 15 minutes to obtain a uniform dispersion.-   5. Seal coated pyridostigmine granules (procedure B) were taken in a    Wurster chamber and coated with the dispersion from step #4, until    target coating weight gain was achieved.

FIG. 1 depicts a schematic representation of pyridostigmine pellets,with and without an immediate release drug layer.

FIG. 5 compares dissolution profiles of pyridostigmine bromide Pellets 2and 3, using USP Apparatus II, in 50 mM of pH 6.8 phosphate buffer. FIG.5 demonstrates that pellets containing pyridostigmine bromide granulesas pellet core provide fast drug release, irrespective of theirfunctional coat weight gain.

Example 5 Pyridostigmine Bromide Pellet Composition Comprising CelletCore

The present Example provides for pyridostigmine bromide pelletcompositions comprising cellet cores. Eight different pellets, asoutlined in Tables 6, 7, and 8, were prepared.

TABLE 6 Formulation of Pyridostigmine Bromide Pellets Pellet 4 Pellet 5Pellet 6 Ingredients mg/dose mg/dose mg/dose Cellet core (350 μm) 100.00100.00 100.00 Drug Layer Pyridostigmine 150.00 150.00 150.00 bromideETHOCEL ® Standard 30.00 30.00 30.00 20 Premium Dibutyl Sebacate 3.003.00 3.00 (DBS) Talc 6.00 6.00 6.00 Solvent* ethanol:water (90:10) q.s.Seal coat METHOCEL ™ E5 72.05 72.05 72.05 Premium LV Talc 14.41 14.4114.41 Solvent* NA NA NA acetone:water (95:5) Functional coat ETHOCEL ®Standard 44.90 112.2 — 20 Premium Dibutyl sebacate 9.00 22.40 — Talc6.70 16.86 — CAB-O-SIL ® 1.10 2.80 — Cellulose acetate — — 89.70(CA-398-10NF/EP) PEG 3350 — — 17.90 METHOCEL ™ E5 Premium LV — — 13.50Solvent* q.s. q.s. q.s. ethanol:water (90:10) Total Weight 437.16 529.72496.56 *Removed during process

TABLE 7 Formulation of Pyridostigmine Bromide Pellets Pellet 7 Pellet 8Ingredients mg/dose mg/dose Cellet core (350 μm) 100.00 100.00 DrugLayer Pyridostigmine bromide 150.00 150.00 ETHOCEL ® Standard 20 Premium30.00 30.00 Dibutyl sebacate (DBS) 3.00 3.00 Talc 6.00 6.00 Solvent*ethanol:water (90:10) q.s. Seal coat METHOCEL ™ E5 Premium LV 16.2016.20 Talc 3.20 3.20 Solvent* acetone:water (95:5) q.s. Functional coatETHOCEL ® Standard 20 Premium 52.30 83.60 Dibutyl sebacate 10.50 16.80Talc 7.80 12.50 METHOCEL ™ E5 Premium LV 5.20 8.40 CAB-O-SIL ® 1.30 3.10Solvent* Acetone:Water (90:10) q.s. Total Weight 385.50 432.80 *Removedduring process

TABLE 8 Formulation of Pyridostigmine Bromide Pellets Pellet 9 Pellet 10Pellet 11 Ingredients mg/dose mg/dose mg/dose Cellet core (350/500 μm)100.0 100.0 100.0 Drug Layer Pyridostigmine bromide 180.0 180.0 180.0ETHOCEL ® Standard 20 Premium 36.00 36.00 36.00 Talc 7.20 7.20 7.20Dibutyl Sebacate (DBS) 3.60 3.60 3.60 Solvent* ethanol:water (90:10)q.s. Seal Coat METHOCEL ™ E5 Premium LV 19.06 19.06 19.06 Talc 3.82 3.823.82 Solvent* acetone:water (95:5) q.s. Functional Coat ETHOCEL ®Standard 20 Premium 56.20 74.94 99.91 Dibutyl Sebacate 11.24 14.99 19.98Talc 8.43 11.24 14.98 METHOCEL ™ E5 Premium LV 1.40 1.87 2.50CAB-O-SIL ® 1.40 1.87 2.50 Solvent* ethanol:water (90:10) q.s. TotalWeight 428.35 454.59 489.55 *Removed during process

Pellets 4-11 contain a cellet core coated with a drug layer containingpyridostigmine bromide and a functional coat over the drug layer;Pellets 4 and 5 contain a functional coat comprising ETHOCEL® Standard20 Premium, dibutyl sebacate, talc, and CAB-O-SIL®; Pellet 6 contains acellet core and a functional coat comprising cellulose acetate 398,polyethylene glycol, and METHOCEL™ E5 Premium LV; and Pellets 7-11contain functional coat comprising ETHOCEL® Standard 20 Premium, dibutylsebacate, talc, METHOCEL™ E5 Premium LV, and CAB-O-SIL®. Pellets 4-11were made according to the following general procedure.

Manufacturing Procedure:

A. Drug Layering

-   1. Pyridostigmine bromide and ETHOCEL® Standard 20 Premium were    added to a mixture of ethanol and water (90:10) and mixed for not    less than about 60 minutes to obtain a solution, followed by    addition of dibutyl sebacate.-   2. To the solution from step #1, talc was added and mixed for not    less than about 30 minutes to obtain a uniform dispersion.-   3. Cellet core was coated using a Wurster fluid bed coater, with an    inlet air temperature of about 25-50° C., and sufficient air volume    for fluidization. When the product temperature reached 30° C., the    dispersion from step #2 was sprayed onto the cellets while    maintaining the product temperature of 25-30° C. and sufficient air    volume for the fluidization, until the target coating weight gain    was achieved.    B. Seal Coating-   1. METHOCEL™ E5 Premium LV was added to a mixture of acetone and    water (95:5) in a stainless steel container and mixed to form a    uniform solution.-   2. To the solution from step #2, talc was added and mixed for not    less than about 30 minutes to obtain a homogeneous dispersion.-   3. Pyridostigmine bromine drug-layered granules (procedure A) were    coated using Wurster fluid bed coater with an inlet air temperature    of 30-50° C., and sufficient air volume for fluidization. When the    product temperature reached 30° C., the dispersion from step #2 was    sprayed onto the drug-layered granules while maintaining the product    temperature of about 28° C. and sufficient air volume for the    fluidization, until the target coating weight gain was achieved.    C. Functional Coating-   1. ETHOCEL® Standard 20 Premium or cellulose acetate 398 (as per    Pellets 4-11) was added to dehydrated alcohol and water or acetone    and water mixture in a stainless steel container and mixed for not    less than about 60 minutes to obtain a uniform solution.-   2. To the solution from step #1, METHOCEL™ E5 Premium LV, and    DBS/PEG were added and mixed until a clear solution was formed.-   3. To the dispersion from step #2, talc and CAB-O-SIL® were added,    and mixed for not less than about 30 minutes to obtain a uniform    dispersion.-   4. Seal coated pyridostigmine pellets (Step B) were taken in a    Wurster chamber and coated with the dispersion from step #3, until    target coating weight gain was achieved.

FIG. 6 compares dissolution profiles of pyridostigmine bromide Pellets9-11, using USP Apparatus II (Paddle), at about 50 rpm and about 37° C.,in 50 mM of pH 6.8 phosphate buffer.

FIG. 6 demonstrates that Pellets 10 and 11, containing higher functionalcoat weight gain, provide better controlled release of pyridostigminebromide for a period of about 22 hours.

Example 6 Effect of the Presence of Orifice in Functional Coat onRelease Rate of Gastroretentive Pyridostigmine Compositions

The present Example provides for comparison of dissolution profiles oftablets comprising pyridostigmine bromide. Three different tablets wereprepared as outlined in Table 9. Tablets were made with and without anorifice in the functional coat to evaluate the effect an orifice has ondissolution profiles.

TABLE 9 Formulation of Pyridostigmine Bromide Gastroretentive TabletsTablet 8 Tablet 13 Tablet 14 Ingredients (mg/dose) (mg/dose) (mg/dose)Tablet Core Pyridostigmine bromide 180.0 135.0 135.0 Succinic acid 50.080.0 80.0 Sodium bicarbonate 50.0 55.0 55.0 Calcium carbonate 125.0 65.065.0 Crospovidone 100.0 100.0 100.0 PARTECK ® M200 233.0 253.0 253.0(D-mannitol) BENECEL ™ K4M PH DC 200.0 — 150.0 METHOCEL ™ K100 — 300.0150.0 Prem LVCR CAB-O-SIL ® 4.00 4.00 4.00 Magnesium stearate 8.00 8.008.00 Total Weight 950.0 1000.0 1000.0 Seal Coat Hydroxypropyl 33.33 — —cellulose Talc 3.33 — — Triethyl citrate 3.33 — — Solvent* q.s. — —acetone:water (95:5) Functional Coat EUDRAGIT ® RL PO 148.15 148.15148.15 Triethyl citrate 22.22 22.22 22.22 Talc 29.63 29.63 29.63Solvent* q.s. q.s. q.s. acetone:water (95:5) Over Coat OPADRY ® white15.0 — — Solvent*Purified q.s. — — water, USP Total Weight 1205.0 1200.01200.0 *Removed during process

Tablet 8 contains 180 mg of pyridostigmine, 50 mg of succinic acid, 50mg of sodium bicarbonate, 125 mg of calcium carbonate, and BENECEL™K4M-DC. Tablets 13 and 14 contain 135 mg of pyridostigmine bromide, 80.0mg of succinic acid, 55.0 mg of sodium bicarbonate, and 65.0 mg ofcalcium carbonate. Further, Tablet 13 contains METHOCEL™ K100 Prem LVCRand Tablet 14 contains a mixture of METHOCEL™ K100 Prem LVCR andBENECEL™ K4M-DC. Tablets 8, 13 and 14, each containing an orifice influid communication with the pull layer, were made according to theprocedure as per Example 2, and without a seal coat step for Tablets 13and 14. FIG. 7 compares dissolution profiles of Tablets 8, 13 and 14 inabout 900 ml of pH 5.0 acetate buffer containing 150 mM NaCl, using USPApparatus I (Custom Basket), at 100 rpm and 37° C. FIG. 7 shows thatTablets 13 and 14 provide 10-15% slower drug release compared to Tablet8.

FIG. 8 compares dissolution profiles, of Tablets 13 and 14 containing anorifice/hole in the membrane/functional coat and Tablets 13 and 14without orifice/hole in the membrane/functional coat. The dissolutiontesting was conducted in about 250 ml of pH 3.0 dissolution mediacontaining about 100 mM NaCl, using USP Apparatus III (BIO-DIS), at 25dpm and 37° C. FIG. 8 demonstrates that Tablets 13 and 14 without anyorifice/hole in the functional coat provided reduced drug recoverycompared to the Tablets 8, 13, and 14 containing an orifice/hole in thefunctional coat.

Example 7 Effect of Coating level of Functional Coat and Presence ofOrifice/Hole in the Functional Coat on Release Rate of GastroretentivePyridostigmine Compositions

The present Example provides for comparison of dissolution profiles oftablets comprising pyridostigmine bromide and various functional coatingcompositions. Three different tablets, as outlined in Table 10, wereprepared. The tablets were tested with and without an orifice/in theirfunctional coat.

TABLE 10 Formulation of Pyridostigmine Bromide Tablets Tablet 8 Tablet14 Tablet 14A Ingredients (mg/dose) (mg/dose) (mg/dose) Tablet CorePyridostigmine bromide 180.0 135.0 135.0 Succinic acid 50.0 80.0 80.0Sodium bicarbonate 50.0 55.0 55.0 Calcium carbonate 125.0 65.0 65.0Crospovidone 100.0 100.0 100.0 PARTECK ® M200 233.0 253.0 253.0BENECEL ™ K4M PH DC 200.0 — 150.0 METHOCEL ™ K100 — 300.0 150.0 PremLVCR CAB-O-SIL ® 4.0 4.00 4.00 Magnesium stearate 8.0 8.00 8.00 TotalWeight 950.0 1000.0 1000.0 Seal Coat Hydroxypropyl 33.33 — — CelluloseTalc 3.33 — — Triethyl citrate 3.33 — — Solvent* q.s. — — acetone:water(95:5) Functional Coat EUDRAGIT ® RL PO 148.15 148.15 185.18 Triethylcitrate 22.22 22.22 27.77 Talc 29.63 29.63 37.03 Solvent* q.s. q.s. q.s.acetone:water (95:5) Total Weight 1190.0 1200.0 1250.0 *Removed duringprocess

Tablets 8 and 14 contain 200 mg coating weight gain of the functionalcoat and Tablet 14A contains 250 mg coating weight gain of thefunctional coat. Tablets 8, 14, and 14A were made according to theprocedure as per Example 2 (and without a seal coat step for Tablets 14and 14A). FIG. 9 compares dissolution profiles, of Tablets 8, 14, and14A containing an orifice/hole in the functional coat and Tablets 14 and14A without orifice/hole in the functional coat. The dissolution testingwas conducted in about 900 ml of pH 5.0 acetate buffer containing 150 mMNaCl, using USP Apparatus I (Custom Basket), at 100 rpm and 37° C. FIG.9 demonstrates that coating weight gain has no significant effect onrelease rate of the tablets. The figure further demonstrates thattablets with orifice/hole provided higher release rate compared totablets without orifice/hole.

Example 8 Effect of Coating Level of Functional Coat and Presence of anOrifice/Hole in the Functional Coat on Floating Lag Time and VolumeExpansion of Gastroretentive Pyridostigmine Compositions

The present example provides for evaluation of floating lag time andvolume expansion of various tablets comprising pyridostigmine bromide.Eight different tablets, as outlined in Tables 11 and 12, were preparedwith various levels of functional coating. The tablets were tested withand without an orifice in their functional coats.

TABLE 11 Formulation of Pyridostigmine Bromide Tablets Tablet 8 Tablet8A Tablet 11 Tablet 11A Ingredients (mg/dose) (mg/dose) (mg/dose)(mg/dose) Tablet Core Pyridostigmine 180.0 180.0 135.0 135.0 bromideSuccinic acid 50.0 50.0 80.0 80.0 Sodium bicarbonate 50.0 50.0 55.0 55.0Calcium carbonate 125.0 125.0 65.0 65.0 Crospovidone 100.0 100.0 200.0200.0 PARTECK ® M200 233.0 233.0 153.0 253.0 BENECEL ™ K4M 200.0 200.0 —150.0 PH DC METHOCEL ™ — — 300.0 150.0 K100 PREM LVCR CAB-O-SIL ® 4.004.00 4.00 4.00 Magnesium stearate 8.00 8.00 8.00 8.00 Total Weight 950.0950.0 1000.0 1000.0 Seal Coat Hydroxypropyl 33.33 33.33 — — celluloseTalc 3.33 3.33 — — Triethyl citrate 3.33 3.33 — — Solvent* q.s. q.s. — —acetone:water (95:5) Functional Coat EUDRAGIT ® RL 148.15 185.18 148.15185.18 PO Triethyl citrate 22.22 27.77 22.22 27.77 Talc 29.63 37.0329.63 37.03 Solvent* q.s. q.s. q.s. q.s. acetone:water (95:5) Over CoatOpadry white 15.0 15.0 — — Total Weight 1205.0 1255.0 1200.0 1250.0*Removed during process

TABLE 12 Formulation of Pyridostigmine Bromide Tablets Tablet 13 Tablet13A Tablet 15 Tablet 15A Ingredients (mg/dose) (mg/dose) (mg/dose)(mg/dose) Tablet Core Pyridostigmine 135.0.0 135.0 135.0 135.0 bromideSuccinic acid 80.0 80.0 125.0 125.0 Sodium bicarbonate 55.0 55.0 75.075.0 Calcium carbonate 65.0 65.0 100.0 100.0 Crospovidone 100.0 100.0200.0 200.0 PARTECK ® M200 253.0 253.0 153.0 153.0 BENECEL ™ K4M — —100.0 100.0 PH DC METHOCEL ™ 300.0 300.0 100.0 100.0 K100 Prem LVCRCAB-O-SIL ® 4.00 4.00 4.00 4.00 Magnesium stearate 8.00 8.00 8.00 8.00Total Weight 1000.0 1000.0 1000.0 1000.0 Functional Coat EUDRAGIT ® RL148.15 185.18 148.15 185.18 PO Triethyl citrate 22.22 27.77 22.22 27.77Talc 29.63 37.03 29.63 37.03 Solvent* acetone:water (95:5) q.s. q.s.q.s. q.s. Total Weight 1200.0 1250.0 1200.0 1250.0 *Removed duringprocess

Tablets 8 and 8A contain 180 mg of pyridostigmine bromide, 50 mg ofsuccinic acid, 50 mg of sodium bicarbonate, 125 mg of calcium carbonate,and a seal coat. Tablets 11 and 11A contain 135 mg of pyridostigminebromide, 80 mg of succinic acid, 55 mg of sodium bicarbonate, and 65 mgof calcium carbonate. Tablets 13 and 13A contain 135 mg ofpyridostigmine bromide, 80 mg of succinic acid, 55 mg of sodiumbicarbonate, and 65 mg of calcium carbonate. Tablets 15 and 15A contain135 mg of pyridostigmine bromide, 125 mg of succinic acid, 75 mg ofsodium bicarbonate, and 100 mg of calcium carbonate. Tablets 8/8A andTablets 13/13A contain 100 mg of crospovidone, and Tablets 11/11A andtablets 15/15A contain 200 mg of crospovidone. Tablets 8, 8A, 11, 11A,13, 13A, 15, and 15A were made according to the procedure as per Example2 (and without a seal coat step for Tablets 11, 11A, 13, 13A, 15, and15A). FIG. 10 compares floating lag time of Tablets 8, 11, 13, and 15,with and without orifice/hole, at 200 mg functional coating weight gain,and Tablets 8A, 11A, 13A, and 15A, with and without orifice/hole, at 250mg functional coating weight gain. The flotation studies were performed,using Rotating Bottle method at 5 rpm and 37° C., in 200 ml of adissolution medium with pH 4.5 acetate buffer containing 100 mM NaCl.The figure demonstrates that tablets with 200 mg functional coatingweight gain exhibit shorter lag time compared to tablets with 250 mgfunctional coating weight gain. The figure further demonstrates thatTablets 8/8A containing a seal coat exhibit longer floating lag timecompared to tablets without a seal coat (Tablets 11/11A, 13/13A, and15/15A).

FIG. 11 compares volumetric expansion at flotation of Tablets 8, 11, 13,and 15, with and without orifice/hole, at 200 mg functional coatingweight gain, and Tablets 8A, 11A, 13A, and 15A, with and withoutorifice/hole, at 250 mg functional coating weight gain. The volumeexpansion studies were performed, using Rotating Bottle method at 5 rpmand 37° C., in 200 ml of pH 4.5 acetate buffer containing 10 mM of NaCl.The figure demonstrates that tablets without orifice/hole exhibit highervolume expansion compared to tablets with orifice/hole.

FIG. 12 compares volumetric expansion, at 90 minutes and at one hour, ofTablets 8, 11, 13, and 15, with and without orifice/hole, at 200 mgfunctional coating weight gain, and Tablets 8A, 11A, 13A, and 15A, withand without orifice/hole, at 250 mg functional coating weight gain. Thevolume expansion studies were performed, using Rotating Bottle method,at 5 rpm and 37° C., in 200 ml of pH 4.5 acetate buffer containing 10 mMof NaCl. The figure demonstrates that tablets without orifice/holeexhibit higher volume expansion compared to tablets with orifice/hole.The figure further demonstrates that the difference in volume expansionbetween tablets with and without a hole is more prominent in tabletswith 200 mg coating weight gain (Tablets 8, 11, 13, 15) compared totablets with 250 mg coating weight gain (Tablets 8A, 11A, 13A, 15A).

FIG. 13 compares volumetric expansion and weight gain at 24 hours, ofTablets 8, 11, 13, and 15, with orifice/hole and without orifice/hole,at 200 mg functional coating weight gain. The volume expansion andweight gain studies were performed, using Rotating Bottle method at 5rpm and 37° C., in 200 ml of pH 4.5 acetate buffer containing 100 mM ofNaCl. FIG. 13 demonstrates that tablets containing 200 mg ofcrospovidone (e.g., Tablets 11/11-H and 15/15-H) exhibit higher weightupon drying compared with tablets containing 100 mg of crospovidone(e.g., Tablets 8/8-H and 13/13-H).

Example 9 Dissolution Profiles of Gastroretentive PyridostigmineCompositions Using BIO-DIS Method

The present Example provides for measurements of dissolution profiles ofvarious gastroretentive pyridostigmine compositions. Five compositions,as outlined in Table 13, were prepared, and tested using BIO-DIS method.

TABLE 13 Formulation of Pyridostigmine Bromide Tablets Tablet 8 Tablet8B Tablet 15 Tablet 16 Tablet 17 Ingredients (mg/dose) (mg/dose)(mg/dose) (mg/dose) (mg/dose) Tablet Core Pyridostigmine 180.0 180.0135.0 135.0 135.0 bromide Succinic acid 50.0 50.0 125.0 125.0 85.0Sodium 50.0 50.0 75.0 75.0 56.0 bicarbonate Calcium 125.0 125.0 100.0100.0 67.0 carbonate Crospovidone 100.0 100.0 200.0 200.0 200.0PARTECK ® 233.0 233.0 153.0 153.0 45.0 M200 BENECEL ™ 200.0 200.0 100.0— — K4M PH DC METHOCEL ™ — — 100.0 200.0 400.0 K100 Prem LVCRCAB-O-SIL ® 4.00 4.00 4.00 4.00 4.00 Magnesium 8.00 8.00 8.00 8.00 8.00stearate Total Weight 950.0 950.0 1000.0 1000.0 1000.0 Seal CoatHydroxypropyl 33.33 33.33 — — — cellulose Talc 3.33 3.33 — — — Triethylcitrate 3.33 3.33 — — — Solvent* q.s. q.s. — — — acetone:water (95:5)Functional Coat EUDRAGIT ® RL 148.15 296.3 148.15 148.15 148.15 POTriethyl citrate 22.22 44.44 22.22 22.22 22.22 Talc 29.63 59.26 29.6329.63 29.63 Solvent* q.s. q.s. q.s. q.s. q.s. acetone:water (95:5) OverCoat OPADRY ® white 15.0 15.0 — — — Solvent*Purified q.s. q.s. water,USP Total Weight 1205.0 1405.0 1200.0 1200.0 1200.0 *Removed duringprocess

Tablets 8, 15, 16, and 17 contain 200 mg functional coating weight gainand Tablet 8B contains 400 mg functional coating weight gain. Tablets 8,8B, 15, 16, and 17 were made according to the procedure as per Example 2(and without the seal coat step for Tablets 15-17). FIG. 14 comparesdissolution profiles of Tablets 8B, 15, 16, and 17 without anorifice/hole and Tablets 8, 8B, 15, 16, and 17 with an orifice/hole.Dissolution studies were performed using BIO-DIS method at 20 dpm and37° C., in 250 ml of pH 3.0 dissolution medium containing 100 mM NaCl.FIG. 14 demonstrates that tablets without an orifice/hole exhibit slowerdrug release compared to tablets with an orifice/hole.

Example 10 Dissolution Profiles of Gastroretentive PyridostigmineCompositions Using USP-I Method

The present Example provides for measurements of dissolution profiles ofvarious gastroretentive pyridostigmine compositions. Three compositionswere prepared as outlined in Table 14 and tested using USP-I method.

TABLE 14 Formulation of Pyridostigmine Bromide Tablets Tablet 8 Tablet18 Tablet 19 Ingredients (mg/dose) (mg/dose) (mg/dose) Tablet CorePyridostigmine bromide 180.0 180.0 180.0 Succinic acid 50.0 125.0 125.0Sodium bicarbonate 50.0 75.0 75.0 Calcium carbonate 125.0 100.0 100.0Crospovidone 100.0 200.0 200.0 PARTECK ® M200 233.0 108.0 108.0BENECEL ® K4M PH DC 200.0 — 100.0 METHOCEL ® K100 — 200.0 100.0 PremiumLVCR CAB-O-SIL ® 4.00 4.00 4.00 Magnesium stearate 8.00 8.00 8.00 TotalWeight 950.0 1000.0 1000.0 Seal Coat Hydroxypropyl cellulose 33.33 — —Talc 3.33 — — Triethyl citrate 3.33 — — Solvent* q.s. q.s. q.s.acetone:water (95:5) Functional Coat EUDRAGIT ® RL PO 148.15 107.15107.15 Triethyl citrate 22.22 21.42 21.42 Talc 29.63 21.42 21.42Solvent* q.s. q.s. q.s. acetone:water (95:5) Over Coat OPADRY ® white15.0 — — Solvent*Purified q.s. water, USP Total Weight 1205.0 1150.01150.0 *Removed during process

Tablet 8 contains 200 mg of BENECEL® K4M PH DC and 100 mg ofcrospovidone, Tablet 18 contains 200 mg of METHOCEL™ and 200 mg ofcrospovidone, and Tablet 19 contains a mixture of 100 mg of METHOCEL™K100 Premium LVCR, and 100 mg of BENECEL® K4M PH DC, and 200 mg ofcrospovidone. Tablets 8, 18, and 19 were made according to the procedureas per Example 2 (and without a seal coat step for Tablets 18 and 19).Tablets 8, 18, and 19 were tested for dissolution in about 900 ml of pH5 acetate buffer, containing 150 mM of NaCl, 30 mM of sodium acetate,and 17 mM of acetic acid, using USP Apparatus I (Custom Basket), at 100rpm and 37° C. FIG. 15 demonstrates that tablets containing 200 mg ofcrospovidone (Tablets 18 and 19) exhibit faster drug release and betterdrug recovery compared to Tablet 8 containing 100 mg of crospovidone.

Example 11 Dissolution Profiles of Gastroretentive PyridostigmineCompositions Using USP-I Method

The present Example provides for measurements of dissolution profiles ofvarious gastroretentive pyridostigmine compositions. Three compositions,as outlined in Table 15, were prepared and tested using USP-I method.

TABLE 15 Formulation of Pyridostigmine Bromide Tablets Tablet 8 Tablet20 Tablet 21 Ingredients (mg/dose) (mg/dose) (mg/dose) Tablet CorePyridostigmine 180.0 305.0 255.0 bromide Succinic acid 50.0 80.0 80.0Sodium bicarbonate 50.0 55.0 55.0 Calcium carbonate 125.0 65.0 65.0Crospovidone 100.0 100.0 100.0 PARTECK ® M200 233.0 73.0.0 123.0BENECEL ® K4M PH DC 200.0 150.0 150.0 METHOCEL ® K100 — 150.0 150.0 PremLVCR CAB-O-SIL ® 4.00 10.00 10.00 Magnesium stearate 8.00 12.00 12.00Total Weight 950.0 1000.0 1000.0 Seal Coat Hydroxypropyl 33.33 — —cellulose Talc 3.33 — — Triethyl citrate 3.33 — — Solvent* q.s. q.s.q.s. acetone:water (95:5) Functional Coat EUDRAGIT ® RL PO 148.15 148.15148.15 Triethyl citrate 22.22 22.22 22.22 Talc 29.63 29.63 29.63Solvent* q.s. q.s. q.s. acetone:water (95:5) Over Coat OPADRY ® white15.0 — — Solvent*Purified q.s. — — water, USP Total Weight 1205.0 1200.01200.0 *Removed during process

Tablet 8 contains 200 mg of BENECEL™, Tablets 20 and 21 contain 150 mgeach of BENECEL™ and METHOCEL™. Tablets 8, 20, and 21 were madeaccording to the procedure as per Example 2 (and without a seal coatstep for Tablets 20 and 21). Tablets 8, 20, and 21 were tested fordissolution in about 900 ml of pH 5.0 acetate buffer containing 150 mMNaCl, using USP Apparatus I (Custom Basket), at 100 rpm and 37° C. FIG.16 demonstrates that tablets containing a mixture of 150 mg each ofBENECEL™ and METHOCEL™ (Tablets 20 and 21) provide more controlledrelease compared to Tablet 8 containing 200 mg of BENECEL™.

Example 12 Dissolution Profiles of Gastroretentive PyridostigmineCompositions Using USP-I Method

The present Example provides for measurements of dissolution profiles ofvarious gastroretentive pyridostigmine compositions. Three compositionswere prepared as outlined in Table 15 and tested using USP-I method.

TABLE 16 Formulation of Pyridostigmine Bromide Tablets Tablet 8 Tablet22 Tablet23 Ingredients (mg/dose) (mg/dose) (mg/dose) Tablet CorePyridostigmine 180.0 135.0 135.0 bromide Succinic acid 50.0 80.0 80.0Sodium bicarbonate 50.0 55.0 55.0 Calcium carbonate 125.0 65.0 65.0Crospovidone 100.0 100.0 100.0 PARTECK ® M200 233.0 249.0 299.0 OxidePigment — — 12.0 Black BENECEL ® K4M 200.0 150.0 150.0 PH DC METHOCEL ®K100 — 150.0 150.0 Prem LVCR CAB-O-SIL ® 4.00 10.00 10.00 Magnesium 8.0012.00 12.00 stearate Total Weight 950.0 1006.0 1068.0 Seal Coat-1Hydroxypropyl 33.33 — — cellulose Talc 3.33 — — Triethyl citrate 3.33 —— Solvent* q.s. — — acetone:water (95:5) Functional Coat EUDRAGIT ® RLPO 148.15 148.15 148.15 Triethyl citrate 22.22 22.22 22.22 Talc 29.6329.63 29.63 Solvent* q.s. q.s. q.s. acetone:water (95:5) Seal Coat-2OPADRY ® II, Clear — — 10.0 Solvent*Purified — — q.s. water, USP DrugLayer Pyridostigmine — — 45.0 bromide Hydroxypropyl — — 9.0 celluloseSolvent*Dehydrated — — q.s. alcohol, Over Coat OPADRY ® white 15.0 —40.0 Solvent*Purified q.s. q.s. water, USP Total Weight 1205.0 1206.01372.0 *Removed during process

Tablet 23 contains an immediate release drug layer. Tablet 8 contains200 mg of BENECEL® K4M PH DC, Tablets 22 and 23 contain 150 mg each ofBENECEL® K4M PH DC and METHOCEL® K100 Prem LVCR. Tablets 8, 22, and 23were made according to the procedure as per Example 2, with thefollowing variations: Tablet 22 and Tablet 23 do not include a seal coatbetween the tablet core and the functional coat, and Tablet 23 wasfurther coated with a seal coat (over the functional coat), an IR druglayer coat, and an over coat as follows:

D. Seal Coat

-   1. OPADRY® Clear was added to purified water in a stainless steel    container and mixed to form a uniform dispersion.-   2. Tablet core 23 with a functional coat was seal coated with the    dispersion from Step 1, using a perforated pan coater with an inlet    air temperature of 25° C.-60° C. at a product temperature of 30-45°    C.    E. IR Drug Layer-   1. Seal coated pyridostigmine bromide tablets from Step D were    further coated with a solution of pyridostigmine bromide,    hydroxypropyl cellulose in dehydrated alcohol, using a perforated    pan coater with an inlet air temperature of 25° C.-60° C. at a    product temperature of 30-45° C.    F. Over Coat-   1. Weighed quantity of OPADRY® white was added to a required amount    of purified water and mixed to obtain a uniform dispersion.-   2. The tablets with IR drug layer from Step E were further coated    with the dispersion from step #1 in a perforated coating pan with    inlet air temperature at 25° C.-45° C.-   3. The coated tablets from step #2 were dried in the coating pan to    a moisture content of below 1.5%.

Tablets 8, 22, and 23 were tested for dissolution in about 900 ml of pH5.0 acetate buffer containing 150 mM of NaCl, using USP Apparatus I(Custom Basket), at 100 rpm and 37° C. FIG. 17 demonstrates that thetablet containing an immediate release drug layer (Tablet 23) eliminateslag time compared to tablets that do not contain an immediate releasedrug layer (Tablets 8 and 22).

Example 13 Additional Gastroretentive Pyridostigmine Compositions

The present Example provides for various gastroretentive pyridostigminecompositions. Ten different compositions were prepared as outlined inTables 17 and 18.

TABLE 17 Formulation of Pyridostigmine Bromide Tablets Tablet 24 Tablet25 Tablet 26 Tablet 27 Tablet 28 Ingredients (mg/dose) (mg/dose)(mg/dose) (mg/dose) (mg/dose) Tablet Core Pyridostigmine 305.0 305.0305.0 255.0 255.0 bromide Succinic acid 80.0 80.0 80.0 80.0 80.0 Sodium55.0 55.0 55.0 55.0 55.0 bicarbonate Calcium carbonate 65.0 65.0 65.065.0 65.0 Crospovidone 100.0 100.0 100.0 100.0 100.0 PARTECK ® 73.0 — —123.0 — M200 BENECEL ® K4M 150.0 186.5.0 236.5 150.0 211.5 PH DCMETHOCEL ® 150.0 186.5 236.5 150.0 211.5 K100 Prem LVCR CAB-O-SIL ®10.00 10.00 10.00 10.00 10.00 Magnesium 12.00 12.00 12.00 12.00 12.00stearate Total Weight 1000.0 1000.0 1100.0 1000.0 1000.0 Functional CoatEUDRAGIT ® 148.15 148.15 148.15 148.15 148.15 RL PO Triethyl 22.22 22.2222.22 22.22 22.22 citrate Talc 29.63 29.63 29.63 29.63 29.63 Solvent*q.s. q.s. q.s. q.s. q.s. acetone:water (95:5) Total Weight 1200.0 1200.01300.0 1200.0 1200.0

TABLE 18 Formulation of Pyridostigmine Bromide Tablets Tablet 29 Tablet30 Tablet 31 Tablet 32 Tablet 33 Ingredients (mg/dose) (mg/dose)(mg/dose) (mg/dose) (mg/dose) Tablet Core Pyridostigmine 70.0 155.0205.0 305.0 100.0 bromide Succinic acid 80.0 80.0 80.0 80.0 80.0 Sodium55.0 55.0 55.0 55.0 55.0 bicarbonate Calcium 65.0 65.0 65.0 65.0 65.0carbonate Crospovidone 100.0 100.0 100.0 100.0 100.0 PARTECK ® 308.0223.0 173.0 — 278.0 M200 BENECEL ® 150.0 150.0 150.0 150.0 150.0 K4M PHDC METHOCEL ® K100 150.0 150.5 150.0 223.0 150.0 Prem LVCR CAB-O-SIL ®10.00 10.00 10.00 10.00 10.0 Magnesium 12.00 12.00 12.00 12.00 12.0stearate Total Weight 1000.0 1000.5 1000.0 1000.0 1000.0 Functional CoatEUDRAGIT ® 148.15 148.15 148.15 148.15 148.15 REPO Triethyl citrate22.22 22.22 22.22 22.22 22.22 Talc 29.63 29.63 29.63 29.63 29.63Solvent* q.s. q.s. q.s. q.s. q.s. acetone:water (95:5) Total Weight1200.0 1200.5 1200.0 1200.0 1200.0 *Removed during process

Tablets 24-26, and 32 contain 305 mg of pyridostigmine bromide; Tablets27 and 28 contain 255 mg of pyridostigmine bromide, Tablet 29 contains70 mg of pyridostigmine bromide, Tablet 30 contains 155 mg ofpyridostigmine bromide, Tablet 31 contains 205 mg of pyridostigminebromide, and Tablet 33 contains 100 mg of pyridostigmine bromide.Tablets 24, 27, 29-31, and Tablet 33 contain 150 mg each of BENECEL® K4MPH DC and METHOCEL® K100 Premium LVCR, Tablet 25 contains 186.5 mg eachof BENECEL® K4M PH DC and METHOCEL® K100 Premium LVCR, Tablet 26contains 236.5 mg each of BENECEL® K4M PH DC and METHOCEL® K100 PremiumLVCR, Tablet 28 contains 211.5 mg each of BENECEL® K4M PH DC andMETHOCEL® K100 Premium LVCR, and Tablet 32 contains 150.0 mg of BENECEL®K4M PH DC and 223.0 mg of METHOCEL® K100 Premium LVCR. Tablets 24-32were made according to the procedure as per Example 2. Tablet 33 is madeaccording to the procedure as per Example 2.

Example 14 Gastroretentive Pyridostigmine Compositions with IR DrugLayer

The present Example provides for gastroretentive pyridostigminecompositions that comprise an immediate release drug layer. Fourdifferent compositions were prepared as outlined in Table 19.

TABLE 19 Formulation of Pyridostigmine Bromide Tablets Tablet 34 (withIngredients hole) Tablet 35 Tablet 36 Tablet 37 Tablet CorePyridostigmine 135.0 135.0 70.00 160.0 bromide Succinic acid 80.0 80.080.0 80.0 Sodium bicarbonate 55.0 55.0 55.0 55.0 Calcium carbonate 65.065.0 65.0 65.0 Crospovidone 100.0 100.0 100.0 100.0 PARTECK ® M200 235.5231.0 278.0 218.0 Oxide Pigment 7.5 12.0 12.0 0 Black BENECEL ® K4M150.0 150.0 150.0 150.0 PH DC METHOCEL ® K100 150.0 150.0 150.0 150.0Prem LVCR CAB-O-SIL ® 10.00 10.00 10.0 10.0 Magnesium stearate 12.0012.00 12.0 12.0 Total Weight 1000.0 1000.0 982.0 1000.0 Functional CoatEUDRAGIT ® RL PO 148.15 148.15 148.15 148.15 Triethyl citrate 22.2222.22 22.22 22.22 Talc 29.63 29.63 29.63 29.63 Solvent* q.s. q.s. q.s.q.s. acetone:water (95:5) Seal Coat OPADRY ® II, Clear 10.0 10.0 10.010.0 Solvent*Purified q.s. q.s. q.s. q.s. water, USP Drug LayerPyridostigmine 45.0 45.0 30.0 20.0 bromide Hydroxypropyl 9.0 9.0 9.0 4.0cellulose Solvent*Dehydrated q.s. q.s. q.s. q.s. alcohol, USP Over CoatOPADRY ® White 40.0 40.0 40.0 40.0 Solvent*Purified q.s. q.s. q.s.water, USP Total Weight 1304.0 1304.0 1271.0 1274.0 *Removed duringprocess

Tablets 34 and 35 contain an immediate release drug layer containing 45mg of pyridostigmine bromide and an extended release component/tabletcore containing 135 mg of pyridostigmine bromide. Tablet 36 contains animmediate release drug layer containing 30 mg of pyridostigmine bromideand an extended release component/tablet core containing 70 mg ofpyridostigmine bromide. Tablet 37 contains an immediate release druglayer containing 20 mg of pyridostigmine bromide and an extended releasecomponent/tablet core containing 160 mg of pyridostigmine bromide.Tablets 34-37 contain 150 mg each of BENECEL® K4M PH DC and METHOCEL®K100 Prem LVCR. Tablets 34, 36, and 37 contain a laser drilled hole inthe functional coat and Tablet 35 is without a hole. Tablets 34, 35, and37 were made as per Tablet 23 in Example 12. Tablet 36 is made as perTablet 23 in Example 12.

Example 15 Oral Bioavailability of Pyridostigmine for Tablet 34(Gastroretentive Dosage Form with Hole)

A single dose pharmacokinetic (PK) study was conducted in healthyvolunteers under fed conditions to evaluate the PK performance ofextended release compositions of the disclosure using Tablet 34. Anopen-label, balanced, nonrandomized, single-dose, two-treatment, one-waycrossover, comparative bioavailability study was conducted in 15 normal,healthy, adult, human subjects under high-fat high-calorie breakfastconditions and under low fat-low calorie conditions.

Pharmacokinetic parameters for pyridostigmine are summarized in Table20.

TABLE 20 Pharmacokinetics Results of Pyridostigmine Mean ± SD (CV %) (N= 15) Pharmacokinetic LF-LC HF-HC parameters (units) (Condition I)(Condition II) C_(max) (ng/mL) 42.178 ± 9.890  45.073 ± 6.094  (23.448)(13.520) AUC_(0-t) (ng · hr/mL) 670.921 ± 287.971 735.1391 ± 173.317 (42.922) (23.576) AUC0-inf (ng · hr/mL) 684.726 ± 292.086 749.674 ±174.634 (42.657) (23.295) T_(max) (hr)* 7.10 ± 3.80 11.0 ± 2.77 (53.55) (25.19)  K_(el) (hr−1) 0.15 ± 0.03 0.15 ± 0.03 (18.90)  (22.02)  t_(1/2)(hr) 4.77 ± 1.03 4.70 ± 1.06 (21.65)  (22.52)  AUC Extrapolated 2.209 ±1.383 2.084 ± 1.657 (%) (62.610) (79.549)

The data from this study (Table 20/FIG. 20) demonstrates that Tablet 34provides a therapeutic plasma concentration of pyridostigmine for atleast about 22 hours.

Example 16 Oral Bioavailability of Pyridostigmine for Tablet 35(Gastroretentive Dosage Form without Hole)

A single dose pharmacokinetic (PK) study was conducted in healthyvolunteers under fed conditions to evaluate the PK performance ofextended release compositions of the disclosure using Tablet 35. Anopen-label, balanced, nonrandomized, single-dose, two-treatment, one-waycrossover, comparative bioavailability study was conducted in 15 normal,healthy, adult, human subjects under high-fat high-calorie breakfastconditions and under low fat-low calorie conditions.

Pharmacokinetic parameters for pyridostigmine are summarized in Table21.

TABLE 21 Pharmacokinetics Results of Pyridostigmine Mean ± SD (CV %) (N= 15) Pharmacokinetic LF-LC HF-HC parameters (units) (Condition I)(Condition II) C_(max) (ng/mL) 47.444 ± 12.070 43.204 ± 13.455 (25.440)(31.144) AUC_(0-t) (ng · hr/mL) 628.282 ± 322.601 761.807 ± 297.513(51.346) (39.054) AUC0-inf (ng · hr/mL) 635.600 ± 336.928 643.820 ±161.166 (53.009) (25.033) T_(max) (hr)* 8.10 ± 6.25 15.44 ± 4.92 (77.14)  (31.85)  K_(el) (hr−1) 0.14 ± 0.04 0.15 ± 0.05 (27.80) (31.12)  t_(1/2) (hr) 5.23 ± 1.61 5.20 ± 2.03 (30.77)  (39.15)  AUCExtrapolated 2.654 ± 2.429 3.621 ± 4.396 (%) (91.528) (121.392) 

The data from this study (Table 21/FIG. 21) demonstrate that Tablet 35provides a therapeutic plasma concentration of pyridostigmine for atleast about 22 hours.

Example 17 Volume Expansion and Texture Analysis/Compressibility forTablet 34 (Gastroretentive Dosage Form with Hole)

Tablet 34 was tested for volume expansion and textureanalysis/compressibility. The volume expansion studies were performedusing Rotating Bottle method, at 5 rpm and 37° C., in 200 ml of 0.001 NHCL containing 10 mM NaCl. FIG. 25A demonstrates that Tablet 34 exhibits100% volume gain at about 30 minutes, 200% volume gain at about 1 hour,and 300% volume gain at 8 about hours post-administration of the tabletinto the dissolution medium. Tablet 34 was simultaneously tested for itstexture/compressibility at various time points using TA.XT^(Plus)apparatus. FIG. 25B demonstrates that the compression force required tosqueeze out the matrix core at 2 hours post-administration, at about200% volume gain, was 30 N; at 8 hours post-administration, at about300% volume gain, was 18.3 N; and at 24 hours post-administration, atabout 250% volume gain, was 4.1 N. It was observed that the tabletmaintained its GRS attributes of floatation and expansion for at leastabout 14 hours, e.g., about 24 hours. The experiment demonstrates thatTablet 34, in its expanded state, e.g., between about 250% and about300% volume gain, can withstand forces of about 10 N until 14 hours, andthe matrix core can be subsequently squeezed thereafter even with forceless than 5 N, after at least about 20 hours, e.g., about 24 hours,post-administration.

What is claimed is:
 1. A gastroretentive dosage form comprising animmediate release layer and an extended release component; wherein theimmediate release layer comprises between about 10 mg and about 60 mgpyridostigmine bromide; and the extended release component comprises acore and a permeable elastic membrane surrounding the core, wherein thecore comprises between about 50 mg and about 400 mg pyridostigminebromide, hypromellose in an amount of between about 5 wt % and about 35wt %, based on the total weight of the core, succinic acid, a carbonatesalt, and a bicarbonate salt, wherein the permeable elastic membranecomprises a plasticizer in an amount of between about 5 wt % and about25 wt % of the membrane, and a copolymer based on ethyl acrylate, methylmethacrylate, and trimethylammonioethyl methacrylate chloride in powderform (1:2:0.2), in an amount of between about 75 wt % and about 95 wt %of the membrane, and wherein the dosage form provides an extendedrelease of pyridostigmine bromide for at least about 14 hours.
 2. Thedosage form of claim 1, wherein the dosage form provides an in vitrorelease of between about 20% and about 35% of the pyridostigmine bromidewithin about 2 hours of dissolution in a dissolution medium comprisingpH 4.5 acetate buffer with 100 mM NaCl.
 3. The dosage form of claim 1,wherein the dosage form floats in about 40 minutes or less in adissolution medium comprising pH 4.5 acetate buffer with 100 mM NaCl. 4.The dosage form of claim 1, wherein the dosage form, when in contactwith gastric fluid, swells in about 60 minutes or less to a size thatprevents its passage through pyloric sphincter.
 5. The dosage form ofclaim 4, wherein the dosage form maintains its integrity in a swollenstate for a period of at least about 14 hours.
 6. The dosage form ofclaim 1, wherein the core further includes crospovidone as a wickingagent.
 7. The dosage form of claim 1, wherein the carbonate andbicarbonate salts comprise CaCO₃ and NaHCO₃, respectively.
 8. The dosageform of claim 1, wherein the plasticizer is triethyl citrate.
 9. Thedosage form of claim 1, wherein the dosage form further includes a sealcoat between the permeable elastic membrane and the immediate releaselayer.
 10. The dosage form of claim 9, wherein the dosage form does notinclude a seal coat between the core and the permeable elastic membrane.11. The dosage form of claim 9, wherein the dosage form further includesan orifice passing through the permeable elastic membrane and the sealcoat.
 12. The dosage form of claim 1, wherein the dosage form is atablet.
 13. The dosage form of claim 12, wherein the dosage form issuitable for once daily administration and is administered as a singletablet/day.
 14. The dosage form of claim 1, wherein the hypromellose isa mixture of a low viscosity hypromellose and a high viscosityhypromellose.
 15. The dosage form of claim 14, wherein the low viscosityhypromellose has a viscosity of between about 80 mPa·s and about 120mPa·s.
 16. The dosage form of claim 14, wherein the high viscosityhypromellose has a viscosity of between about, 2,700 mPa·s and about5,040 mPa·s.
 17. The dosage form of claim 1, wherein the hypromellose isa high viscosity hypromellose having a viscosity of between about 2,700mPa·s and about 5,040 mPa·s.
 18. A gastroretentive dosage formcomprising an immediate release layer and an extended release component;wherein the immediate release layer comprises between about 10 mg andabout 60 mg pyridostigmine bromide; and the extended release componentcomprises a core and a permeable elastic membrane surrounding the core,wherein the core comprises between about 50 mg and about 400 mgpyridostigmine bromide, a high viscosity hypromellose in an amount ofbetween about 5 wt % and about 35 wt %, based on the total weight of thecore, succinic acid, a carbonate salt, and a bicarbonate salt, whereinthe high viscosity hypromellose has a viscosity of between about, 2,700mPa·s and about 5,040 mPa·s, wherein each of sodium bicarbonate andcalcium carbonate is present in equimolar amounts with respect tosuccinic acid, wherein each of sodium bicarbonate, calcium carbonate,and succinic acid is present in an amount of between about 1 wt % andabout 10 wt %, based on the total weight of the core, wherein thepermeable elastic membrane comprises a plasticizer in an amount ofbetween about 5 wt % and about 25 wt % of the membrane composition, anda copolymer based on ethyl acrylate, methyl methacrylate, andtrimethylammonioethyl methacrylate chloride in powder form (1:2:0.2), inan amount of between about 75 wt % and about 95 wt % of the membranecomposition, and wherein the dosage form floats in about 40 minutes orless in pH 4.5 acetate buffer with 100 mM NaCl.
 19. A gastroretentivedosage form comprising a core and a permeable elastic membranesurrounding the core, wherein the core comprises between about 50 mg andabout 400 mg pyridostigmine bromide, hypromellose in an amount ofbetween about 5 wt % and about 35 wt %, based on the total weight of thecore, succinic acid, a carbonate salt, and a bicarbonate salt, whereinthe hypromellose has a viscosity of between about, 2,700 mPa·s and about5,040 mPa·s, wherein each of sodium bicarbonate and calcium carbonate ispresent in equimolar amounts with respect to succinic acid, wherein eachof sodium bicarbonate, calcium carbonate, and succinic acid is presentin an amount of between about 1 wt % and about 10 wt %, based on thetotal weight of the core, wherein the permeable elastic membranecomprises a plasticizer in an amount of between about 5 wt % and about25 wt % of the membrane composition, and a copolymer based on ethylacrylate, methyl methacrylate, and trimethylammonioethyl methacrylatechloride in powder form (1:2:0.2), in an amount of between about 75 wt %and about 95 wt % of the membrane composition, wherein the dosage formfloats in about 40 minutes or less in pH 4.5 acetate buffer with 100 mMNaCl, and wherein the dosage form provides an extended release ofpyridostigmine bromide for at least about 14 hours.